
==== Front
J Adv Res
J Adv Res
Journal of Advanced Research
2090-1232
2090-1224
Elsevier

S2090-1232(23)00321-1
10.1016/j.jare.2023.10.015
Medicine
CC chemokines Modulate Immune responses in Pulmonary Hypertension
Yan Qian a
Liu Shasha b
Sun Yang a
Chen Chen c
Yang Yantao a
Yang Songwei a
Lin Meiyu a
Long Junpeng a
Lin Yuting a
Liang Jinping a
Ai Qidi 278339420@qq.com
a⁎
Chen Naihong chennh@imm.ac.cn
ad⁎
a Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
b Department of Pharmacy, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha 410007, China
c Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China
d State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
⁎ Corresponding authors at: Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China (Q. Ai and N. Chen). 278339420@qq.comchennh@imm.ac.cn
04 11 2023
9 2024
04 11 2023
63 171186
8 8 2023
24 10 2023
31 10 2023
© 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo University.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Graphical abstract

Highlights

• The immune response and inflammation in pulmonary hypertension (PH) have been systematically summarized based on recent studies.

• The relationship between CC chemokines and the pathogenesis of pH is summarized in clinical and animal models.

• We found that although the immune response serves as an important potential factor in the pathogenesis of PH, less attention has been paid to CC chemokines and their receptors.

• We believe that a greater understanding of the relationship between PH and CC chemokines and their receptors is a pressing issue.

• We believe that we need to further clarify the pathogenesis of pH and provide basis for the clinical treatment of PH.

Background

Pulmonary hypertension (PH) represents a progressive condition characterized by the remodeling of pulmonary arteries, ultimately culminating in right heart failure and increased mortality rates. Substantial evidence has elucidated the pivotal role of perivascular inflammatory factors and immune dysregulation in the pathogenesis of PH. Chemokines, a class of small secreted proteins, exert precise control over immune cell recruitment and functionality, particularly with respect to their migration to sites of inflammation. Consequently, chemokines emerge as critical drivers facilitating immune cell infiltration into the pulmonary tissue during inflammatory responses. This review comprehensively examines the significant contributions of CC chemokines in the maintenance of immune cell homeostasis and their pivotal role in regulating inflammatory responses. The central focus of this discussion is directed towards elucidating the precise immunoregulatory actions of CC chemokines concerning various immune cell types, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils, particularly in the context of pH processes. Furthermore, this paper delves into an exploration of the underlying pathogenic mechanisms that underpin the development of PH. Specifically, it investigates processes such as cellular pyroptosis, examines the intricate crosstalk between bone morphogenetic protein receptor type 2 (BMPR2) mutations and the immune response, and sheds light on key signaling pathways involved in the inflammatory response. These aspects are deemed critical in enhancing our understanding of the complex pathophysiology of PH. Moreover, this review provides a comprehensive synthesis of findings from experimental investigations targeting immune cells and CC chemokines. Aim of review: In summary, the inquiry into the inflammatory responses mediated by CC chemokines and their corresponding receptors, and their potential in modulating immune reactions, holds promise as a prospective avenue for addressing PH. The potential inhibition of CC chemokines and their receptors stands as a viable strategy to attenuate the inflammatory cascade and ameliorate the pathological manifestations of PH. Nonetheless, it is essential to acknowledge the current state of clinical trials and the ensuing progress, which regrettably appears to be less than encouraging. Substantial hurdles exist in the successful translation of research findings into clinical applications. The intention is that such emphasis could potentially foster the advancement of potent therapeutic agents presently in the process of clinical evaluation. This, in turn, may further bolster the potential for effective management of PH.

Keywords

Pulmonary hypertension
CC chemokines
Immune cell
Inflammation
==== Body
pmcIntroduction

PH is a pathological condition characterized by an anomalous elevation in vascular pressure within the pulmonary circulation, typically indicated by mean pulmonary artery pressures exceeding 20 mmHg [1], [2]. Specifically, the circulatory system facilitates the transfer of blood from the heart to the lungs, serving to sustain regular physiological activities. However, when a multitude of factors or stimuli, such as hypoxia and inflammation, elevate the pressure within the pulmonary artery, it leads to a deceleration of the right ventricular pumping. Consequently, this phenomenon can precipitate right ventricular hypertrophy, hypoxia, and potentially fatal outcomes [3].

The pathogenesis of pH is recognized for its multifaceted characteristics, encompassing a diverse spectrum of etiological factors and underlying mechanisms. PH is systematically categorized into five distinct classes, specifically pulmonary arterial hypertension (PAH), PH associated with left heart disease, PH associated with lung disease, PH associated with pulmonary arterial obstruction, and PH with indeterminate and/or multifactorial mechanisms [2]. A synthesis of previous investigations pertaining to the role of CC chemokine regulation in the progression of pH highlights the extensive examination of CC chemokine ligands (CCL)2 and CCL5. Notably, CCL2 deficiency has exhibited an ameliorative effect on the pulmonary immune-inflammatory response and pulmonary vascular remodeling in patients afflicted with chronic thromboembolic pulmonary hypertension (CTEPH) [4], PAH [5], bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) [6], idiopathic PAH (IPAH) [7], as well as in pertinent animal models. In parallel, deficiency in CCL5 has similarly demonstrated a propensity to enhance the pulmonary immune-inflammatory response and pulmonary vascular remodeling in patients with CTEPH [4], PAH [8], and hypoxia-induced PH [7], alongside relevant animal models. Moreover, CCL5 deficiency has been found to instigate the activation of the bone morphogenetic protein (BMP) signaling pathway, serving to impede the progression of PAH. The interplay between CCL19-CCL21 and the receptor CC chemokine receptor (CCR)7 has been implicated in triggering an inflammatory response within the pulmonary system, thereby inducing pulmonary vascular injury in the context of systemic sclerosis (SSc). This interplay has emerged as a promising indicator for the risk assessment of SSc-associated PAH[9].

The innate immune response is characterized by a triphasic sequence comprising the inflammatory phase, proliferative phase, and maturation phase. The initial trigger and subsequent consequence in the development of cardiovascular disease are encompassed within the inflammatory phase. Throughout these phases, intracellular contents are released, leading to the degradation of the extracellular matrix and the generation of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). The activation of immune cells follows the engagement of cytoplasmic pattern recognition receptors (PRRs), also known as inflammatory vesicle sensors, located on the cell surface [10]. This intricate process is exemplified in the context of cardiovascular disease, where the initial inflammatory response prompts the activation of fibroblasts of external origin. These activated fibroblasts subsequently initiate the secretion of cytokines and chemokines, thus facilitating the recruitment of immune cells to the vessel wall. The ensuing activation of these immune cells, influenced by cytokines and chemokines, perpetuates the inflammatory cascades. Consequently, these cascades induce endothelial cell proliferation, smooth muscle cell migration, fibroblast activation, and significantly contribute to the process of vascular remodeling [11].

The integral roles played by both the inflammatory and immune systems in the pathogenesis and progression of pH have received substantial emphasis. This assertion finds robust support in recent evidence derived from diverse sources, including epidemiological studies, biomarker analyses, genetic investigations, animal models, and clinical trials [12]. Significantly, pulmonary biopsies obtained from tissues of patients diagnosed with PAH have unveiled the presence of diverse inflammatory cell types residing in close proximity to the remodeled pulmonary vascular system. These discernible cell lineages encompass monocytes/macrophages, neutrophils, T lymphocytes/B lymphocytes, dendritic cells, as well as mast cells, eosinophils, and basophils [13]. The accumulation of inflammatory cells in the perivascular regions of pulmonary blood vessels plays a pivotal role in exacerbating pulmonary vascular remodeling and exerts a substantial influence on pulmonary hemodynamics [13]. Moreover, immune cells display a notable predilection for aggregating in the vicinity of pulmonary vasculature and plexiform lesions. This aberrant accumulation of immune cells can incite inflammatory responses, leading to heightened levels of proinflammatory cytokines and chemokines, consequently contributing to the process of pulmonary vascular remodeling [14].

In the context of PH, chemokines play a crucial role in facilitating the infiltration of immune cells into the lungs during the inflammatory response. Notably, regulatory T cells assume a significant function in curbing inflammation and restraining cell proliferation in PH through the secretion of cytokines and chemokines [14]. The involvement of CC chemokines and their corresponding receptors is pivotal in the intricate regulation of immune cell recruitment and function. This regulatory mechanism significantly influences both the onset and progression of the disease [15], [16]. Robust research findings consistently demonstrate the upregulation of CC chemokines and their associated receptors within the pulmonary environment. This upregulation contributes to the pathogenesis of various lung ailments, such as asthma [17], PH [15], and chronic obstructive pulmonary disease [18]. Consequently, the dysregulation of chemokine signaling presents a plausible mechanism underlying the advancement of PH (Fig. 1)Fig. 1 CC chemokines play a critical role in modulating the accumulation of immune cells within the lung, thus promoting inflammatory responses. The recruitment of immune cells by CC chemokines and their corresponding receptors results in their aggregation within the lung, thereby instigating an inflammatory cascade. The pathogenesis of pH is intricately associated with pyroptosis, genetic mutations, hypoxia, inflammation, and their respective signaling pathways. The immune-inflammatory reaction releases elevated levels of pro- inflammatory factors, subsequently inducing endothelial dysfunction, cell proliferation, and cell migration, thereby exacerbating the inflammatory response. These processes collectively contribute to the worsening of the PH pathological progression.

This article is focused on the regulatory role of CC chemokines and their receptors in modulating immune cells and immune-inflammatory mechanisms, thereby influencing the progression of PH. It succinctly delineates the involvement of CC chemokines and their receptors in the immune processes underlying PH, encompassing their role in immune cell recruitment and chemotaxis. Furthermore, recent investigations into the relevant pathogenesis and signaling pathways impacted by CC chemokines and their receptors are outlined, shedding light on their contribution to the advancement of PH. Finally, this section offers an overview of the potential advantages and limitations associated with the utilization of CC chemokines as promising targets for tailored PH therapy. Additionally, a compendium of therapeutic agents capable of targeting CC chemokines is presented, albeit without the inclusion of clinical trial outcomes.

Chemokines and CC chemokines

Chemokines represent a category of small, secreted proteins, typically characterized by mass ranging from approximately 8 to 13 kDa. These proteins play pivotal roles in orchestrating essential processes related to the regulation of targeted cell migration, adhesion, cellular localization, and intercellular interactions. The mechanistic basis of these functions is rooted in chemokines binding to chemokine receptors, a family of Gαi protein-coupled seven-transmembrane receptors situated on the cell membrane [19]. The primary and widely recognized regulatory role of chemokines lies in their capacity to govern the infiltration of immune cells in the context of inflammatory and immune-related diseases. This regulatory function is achieved through the establishment of concentration gradients, which may be in a soluble or immobilized form, thereby directing the precise movement of immune cells to specific anatomical sites. This finely tuned modulation of immune cell migration stands as a central and indispensable mechanism in both the establishment and sustenance of immune system homeostasis.

The chemokine protein family displays a remarkably conserved structural pattern characterized by a three-chain β-fold structure and a C-terminal α-helix, exhibiting an average sequence homology ranging from approximately 20 % to 50 %. Classification of chemokines is based on the specific arrangement of two cysteine residues at the N-terminus, resulting in the delineation of four distinct subfamilies: CC chemokines, CXC chemokines, CX3C chemokines, and C chemokines [20], [21]. In contrast, chemokine receptors exhibit distinct patterns of expression across various cell types and can be broadly categorized into two primary groups: G protein-coupled chemokine receptors (GPCRs) and atypical chemokine receptors. The interaction between chemokines and their receptors, which encompasses a repertoire of over 20 chemokine receptors, predominantly occurs through interactions with GPCRs [21]. CC chemokines are characterized by the distinctive arrangement of two N-terminal cysteine residues in close proximity. Within this subfamily, a notable diversity is observed, encompassing a minimum of 28 distinct members, referred to as CCL 1–28. These CC chemokines exert their signaling influences through interactions with a well-defined group of 10 chemokine receptors, denoted as CCR 1–10 [22].

Role of CC chemokines/cytokines in the PH immune response

CC chemokines find predominant expression in immune cell types intricately linked with inflammatory processes. Their heightened production significantly contributes to the sustained infiltration of immune cells into inflamed regions. Acute inflammation, initiated by factors such as injury, irritation, and infection of pulmonary vascular tissues, promptly triggers the attraction of cells and molecules associated with the innate immune response to potential sites of microbial infection. This process results in the formation of inflammatory exudates. The orchestrated recruitment of immune cells plays a pivotal role in regulating tissue inflammation and coordinating subsequent reparative processes. This recruitment unfolds in a sequential fashion, commencing with the recruitment of neutrophils and subsequently followed by the recruitment of monocytes, which subsequently undergo differentiation into macrophages [22]. Hence, CC chemokines play a pivotal role as critical mediators in the recruitment of monocytes and the subsequent differentiation of these monocytes into macrophages.

In the context of pulmonary vascular pathology, dysregulated synthesis of pulmonary artery fibroblasts, endothelial cells, and smooth muscle cells can lead to the abnormal expression of CC chemokines and their corresponding receptors. This dysregulation is closely associated with heightened cellular proliferation and migration processes, which, in turn, substantially contribute to the pathogenesis of PH [21]. More specifically, within lung endothelial cells, the release of chemokines leads to the creation of a chemoattractant gradient. This gradient, in turn, facilitates the processes of immune cell rolling, adhesion, and subsequent extravasation. These events collectively underscore the integral role of chemokines in the inflammatory response that underlies the pathophysiology of PH [21].

Recent research has unveiled the potentially beneficial impact of manipulating or inhibiting CC chemokines and their corresponding receptors in experimental animal models of PH. For instance, in a study conducted by Abid S. et al., it was observed that mice exposed to chronic hypoxia, resulting in the development of PH, exhibited notable overexpression of CCR2 and CCR5 in macrophages and pulmonary artery smooth muscle cells (PASMCs). Intriguingly, the inhibition of either CCR2 or CCR5 demonstrated a marked attenuation of pH progression. However, dual inhibition of both CCR2 and CCR5 proved to be even more effective, not only in preventing the onset of pH but also in reversing its development [15]. These findings substantiate the involvement of the interaction between macrophages and PASMCs, mediated through CCR2 and CCR5, in the development and progression of PH. In the context of PH, M1 macrophages exhibit proinflammatory characteristics, while M2 macrophages promote cytokinesis and proliferation. The heightened induction of inflammation orchestrated by CC chemokines and their receptors contributes to the promotion of a proliferative phenotype among PASMCs during PH, thereby facilitating the remodeling of pulmonary vascular tissue. Furthermore, another study conducted by Amsellem V. et al. furnishes direct evidence indicating that interventions targeting CC chemokines and their receptors within PH therapy exert an impact not only on the activation of inflammatory cells but also directly influence the remodeling processes within the constitutive vascular cell population [16]. These findings underscore the intricate and multifaceted regulatory roles played by CC chemokines and their corresponding receptors in the context of PH. These roles encompass not only the activation of inflammatory cells but also extend to the modulation of vascular cell remodeling processes.

Elevated expression levels of numerous cytokines, including but not limited to interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α), assume a crucial role in directly stimulating the proliferation, migration, and differentiation of pulmonary vascular cells. For instance, in a study conducted by Sánchez-Gloria JL and colleagues, elevated protein expression levels of TNF-α, IL-1β, and IL-6 were demonstrated in a rat model of pH induced by monocrotaline (MCT) [23]. Moreover, their research revealed that exposure to cold temperatures exacerbates the expression of these pro-inflammatory cytokines. Additionally, Huang Y. et al. established a robust association between cytokine and chemokine signaling, as evidenced by RNA sequencing data obtained from rat lung samples [24]. Concurrently, Ross DJ et al. conducted an investigation into the expression levels of cytokines and chemokines in the plasma of patients diagnosed with PH utilizing enzyme-linked immunosorbent assay. Their findings provided substantive evidence that the interplay between these molecules not only fosters inflammation but also contributes to the pathogenesis of PH [25]. Furthermore, Sheng Y and colleagues made a notable discovery wherein they identified that the CC chemokine signaling pathway acts as a stimulant for the production of cytokines associated with inflammation, such as IL-1β, IL-6, and TNF-α [5]. Regrettably, existing research has not provided conclusive evidence to definitively establish CC chemokines as mediators of this particular signaling pathway. Hypotheses regarding their potential involvement have been derived from a limited number of experimental findings, suggesting potential associations with pathways such as the nuclear factor kappa-B (NF-κB) signaling pathway, Smad signaling pathway, and TNF signaling pathway [5], [26], [27].

The role of CC chemokines in the pathogenesis of PH

CC chemokines mediate pyroptosis

Pyroptosis represents a form of programmed cell death distinguished by an associated inflammatory reaction [28]. It is instigated by the aggregation of inflammatory vesicles, triggered through the activation of cell surface PRRs in response to diverse PAMPs and DAMPs [29]. Notably, PRRs encompass TLRs, C-type lectin-like receptors, and cytoplasmic PRRs, such as nucleotide-binding oligomerization domain (NOD)-like receptors, which recognize invading pathogens [30]. Within the canonical inflammasome pathway, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome complex consists of NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1 [31]. Stimulation of the NLRP3 inflammasome by various stimuli prompts the self-cleavage of pro-caspase-1, resulting in the activation of caspase-1. Active caspase-1 subsequently cleaves inactive forms of IL-1β and IL-18, along with gasdermin D (GSDMD), leading to the generation of their active forms and the creation of GSDMD pores. This sequence culminates in pyroptosis and the instigation of inflammatory responses [32]. Pyroptosis primarily occurs in immune cells and is distinguished by the rapid disruption of the plasma membrane and the release of pro-inflammatory contents [33].

The disruption of membrane pores subsequent to cellular pyroptosis results in the liberation of pro-inflammatory factors, notably IL-18 and IL-1β. Initially, these factors elicit alterations in lung fibroblasts, culminating in the exacerbation of pulmonary vascular remodeling. Furthermore, the expression of pro-inflammatory factors fosters the accumulation of immune cells in the lung, thereby intensifying the inflammatory response and contributing to pulmonary vascular remodeling [34]. Consequently, the inflammatory reaction incited by cellular pyroptosis contributes to the progression of PH, with its implications extending beyond PH linked solely to immune system disorders. Additionally, the activation of the NLRP3 inflammasome is contingent upon toll-like receptors (TLR) agonists, which induce the expression of IL-1β and NLRP3 via the MyD88-NF-κB pathway, thus fostering the promotion and upregulation of pro-inflammatory mediators [31].

While no direct evidence currently supports the precise mechanism by which CC chemokines and their ligands regulate cellular pyroptosis to modulate PH, it is postulated based on existing literature. Firstly, it is proposed that CC chemokines can activate the NF-κB pathway, thereby enhancing the expression levels of inflammatory mediators that contribute to the progression of PH. Following multifaceted activation of the NLRP3 inflammasome within the NF-κB pathway, PRRs trigger the activation of caspase-1 through self-cleavage. Active caspase-1 not only cleaves inactive IL-1β and IL-18 precursors but also cleaves GSDMD, leading to the liberation of GSDMD-NT and the subsequent formation of pores, ultimately instigating the inflammatory response and pyroptosis in the context of PH [32]. Secondly, it is posited that cellular pyroptosis is activated via the NF-κB/NLRP3 pathway, releasing inflammatory mediators that further stimulate inflammatory responses and pulmonary artery remodeling. Concurrently, the NF-κB/NLRP3 pathway augments the expression of CC chemokines, which subsequently facilitate the recruitment of immune cells to accumulate within the lung, thereby mediating cellular pyroptosis via the NF-κB/NLRP3 pathway [35].

The inhibition of pyroptosis and concurrent vascular remodeling in models of PH, particularly those involving PASMCs and pulmonary artery endothelial cells (PAECs), has emerged as a promising therapeutic strategy for PH. Zhang et al. illustrated the occurrence of pyroptosis in the pulmonary artery media of two PH rat models and in hypoxic human PASMCs. Their findings indicated that the inhibition of Caspase-1, a pivotal element in the process of pyroptosis, effectively mitigated the progression of pH and ameliorated vascular remodeling [36]. Additionally, it has been observed that pyroptosis exacerbates the disruption of BMPR2 signaling, thereby contributing to the advancement of PH [37]. Collectively, these investigations suggest that the targeted intervention of pyroptosis and its associated pathways represents a significant therapeutic avenue for addressing PH.

CC chemokines mediate gene mutations

PH is distinguished by a progressive remodeling of the peripheral pulmonary arteries, encompassing the excessive proliferation of endothelial cells, smooth muscle cells, and fibroblasts, alongside perivascular inflammation. The pathophysiological framework of pH involves diverse cellular and molecular irregularities, including loss-of-function mutations within the BMPR2 gene and immune responses [38]. BMPR2 assumes a crucial role in maintaining pulmonary vascular homeostasis and is commonly associated with familial instances of PH [39]. (Fig. 3) Notably, the pathogenicity of BMPR2 mutations exhibits gender-specific disparities, with males demonstrating a lower penetrance rate relative to females, potentially influenced by estrogen metabolism [40]. While a comprehensive understanding of the interplay between BMPR2 mutations and environmental factors necessitates further exploration, a plethora of studies have underscored the significance of inflammatory mediators in BMPR2-related PH [40]. Notably, mice lacking BMPR2 display an elevated production of inflammatory cytokines and heightened proliferation of PASMCs following exposure to lipopolysaccharide [41]. Hurst et al. revealed that the inflammatory cytokine TNF-α contributes to the progression of PAH by suppressing vascular BMPR2 transcription and promoting BMPR-II cleavage in PASMCs. In the context of BMPR2 mutations or deficiency, TNF-α triggers aberrant expression of Neurogenic locus notch homolog protein 2, subsequently activating downstream HEY1/2 signaling and fostering PASMC proliferation. This establishes a mechanistic association between BMPR2 and inflammatory mediators [42]. Moreover, disruptions in chemokine signaling are emerging as potential contributors to the development of PH. As previously mentioned, chemokines exert a substantial influence on the recruitment and regulation of immune cells at sites of inflammation, modulating both pro-inflammatory and anti-inflammatory responses. Hence, it is imperative to consider the involvement of chemokines in the intricate interplay between BMPR2 downregulation or deletion and inflammatory responses. Notably, augmented levels of CCL2 have been observed in lung tissue within a PH model featuring dominant-negative BMPR2 mice [21]. Conversely, the silencing of the CCL5/CCR5 signaling axis activated BMPR2 expression, thereby rescuing PAH and mitigating pulmonary artery occlusion [8].

CC chemokines mediate hypoxia.

Hypoxia-inducible factor (HIF) serves as a critical regulator of oxygen homeostasis, orchestrating diverse cellular responses, including lung cell proliferation, thereby contributing to vascular remodeling. (Fig. 3) This process primarily involves the nuclear translocation of the HIF-α subunit and its binding to the HIF-β subunit [43]. Amidst various signaling pathway dysregulations implicated in the exacerbation of PH, HIF signaling has emerged as a pivotal mechanism influencing disease progression, extending beyond hypoxia-induced PH subtypes. Extensive investigations have shed light on the role of the CCL2 chemokine and its receptor CCR2 signaling axis in hypoxia-induced PH. Yu et al. conducted experiments exposing CCR2-deficient mice to chronic low-pressure hypoxia, demonstrating that these mice developed more severe PAH and exhibited augmented muscularization of the small pulmonary arteries relative to their wild-type counterparts [44]. Notably, CCR2-deficient mice displayed a propensity for spontaneous PAH development over time. Under hypoxic stress, these mice manifested an accumulation of monocyte-derived DCs and macrophages proximal to the pulmonary vasculature, with no significant alterations observed in T cell populations. Furthermore, the involvement of the Notch signaling pathway in PAH development in CCR2-deficient mice was underscored, evidenced by a five-fold increase in Notch-3 expression compared to wild mice under hypoxic conditions [44]. Amsellem et al.'s research further supports the concept that chemokine deficiency exacerbates PH during hypoxia [45]. This study elucidated an escalation in pulmonary monocytes and macrophages in response to chemokine deficiency during hypoxia, emphasizing the direct engagement of myeloid cells, particularly those of the non-classical monocyte lineage, in the pathogenesis of PH. Myeloid cells, sensitive to hypoxia, aggregate in small pulmonary arteries, thereby fostering pulmonary vascular remodeling [46]. Moreover, the exacerbation of pH subsequent to platelet activation in the hypoxia-induced PH model warrants specific attention [47]. Following exposure to hypoxia, elevated plasma levels of CCL5 and platelet activation were observed in the PH model. Platelet activation contributes to PH pathogenesis through platelet-endothelial adhesion, further amplifying vascular remodeling. Notably, platelet depletion was shown to curtail plasma pro-inflammatory chemokine expression and lung macrophage accumulation in the hypoxia-induced PH model [48].

Neutrophils and CC chemokines in PH

Neutrophils are acknowledged as the principal responders during episodes of acute inflammation and have additionally been implicated in chronic inflammatory processes. These immune cells exhibit a consistent propensity to migrate toward sites of inflammation and play an active role in the inflammatory cascade. Neutrophils exert their influence through a multitude of mechanisms, including the release of serine proteases, the formation of neutrophil extracellular traps, and the activation of other immune cells [49]. Through these various actions, neutrophils assume a central role in driving the inflammatory process and play a pivotal role in orchestrating immune responses.

Endothelial dysfunction occurring within the pulmonary vasculature is widely acknowledged as a triggering factor for vascular remodeling in the context of PH. Neutrophils, functioning as a defense mechanism against microbial invasion, must traverse the blood-endothelial cell barrier to reach sites of inflammation. Nevertheless, the infiltration of neutrophils into tissues necessitates meticulous regulation to ensure both effective pathogen eradication and tissue repair. Excessive accumulation of neutrophils can lead to consequential tissue damage [50]. The interplay between monocytes/macrophages and neutrophils assumes a pivotal role in the promotion of inflammation, frequently associated with an excessive infiltration of neutrophils into tissues. Tissue-resident macrophages undertake the activation and recruitment of neutrophils to sites of inflammation through the secretion of chemotactic agents, including CC chemokine ligands. Subsequently, neutrophils migrate to the site of inflammation and actively contribute to the inflammatory response by releasing an array of proteins that serve to recruit monocytes [49]. Significantly, upon migration to sites of inflammation, neutrophils undergo upregulation of the expression of several chemokines, among them CC chemokines. This underscores their active engagement in the inflammatory process, consequently amplifying their role in the pathogenesis of PH [49].

CC chemokines assume a pivotal pro-inflammatory role by serving as strategically targeted agents that guide neutrophil recruitment to precise anatomical sites, notably the lungs. In the context of neutrophil recruitment to the pulmonary region, key CC chemokine ligands implicated in this orchestration include CCL2, CCL5 and CCL8. These chemokines act as potent chemoattractants, intricately directing the migration of neutrophils to the lungs during inflammatory responses. By exerting selective control over neutrophil migration, CC chemokines significantly contribute to the meticulous regulation of the inflammatory process and its precise localization within the lung microenvironment.

In a histopathological examination delving into pulmonary vascular lesions among individuals afflicted by chronic thromboembolic PH, Quarck R et al. [51] documented a notable accumulation of inflammatory cells, notably including neutrophils, macrophages, and T lymphocytes. Furthermore, elevated levels of diverse inflammatory mediators, including CCL2, were identified in the plasma of individuals afflicted by CTEPH. In a separate investigation conducted by Fu J et al., the researchers delved into the realm of inflammation and pulmonary artery remodeling, utilizing a rat model with PH induced by MCT [52]. The lungs of rats induced with MCT exhibited a significantly elevated presence of neutrophils in comparison to the lungs of normal rats. Subsequently, the MCT-induced rats underwent treatment IL-8 receptors. Notably, the targeted delivery of overexpressed IL-8 receptors by PAECs yielded noteworthy results, manifesting in a substantial reduction in neutrophil infiltration. Furthermore, this intervention was associated with a decrease in the protein content of key inflammatory mediators, including CCL2, CCL3 and CCL8, within the lungs. Additionally, this therapeutic approach elicited a favorable impact on pulmonary vascular remodeling within the MCT-induced rat model [52]. Collectively, these findings underscore the intricate relationship between neutrophil infiltration, inflammatory mediators, and the advancement of pulmonary vascular pathologies. The studies offer valuable insights into potential therapeutic strategies that entail the precise modulation of specific chemokine receptors. Such approaches hold the promise of attenuating neutrophil-driven inflammation and fostering beneficial pulmonary vascular remodeling in the context of PH.

Monocytes/Macrophages and CC chemokines in PH

Hematopoietic stem cells (HSCs) are responsible for orchestrating the differentiation of hematopoietic lineages within the human bone marrow. HSCs give rise to two distinct types of progenitor cells known as common myeloid progenitor cells (CMPs) and common lymphoid progenitor cells (CLPs). CMPs possess the capability to generate “neutrophil-like” inflammatory monocytes and granulocytes. Additionally, within the CMP lineage, there exists a monocyte-macrophage/dendritic lineage-restricted progenitor (MDP) stage, which can further differentiate into common dendritic progenitor (CDP) cells, subsequently culminating in the development of dendritic cells (DCs). Recent revisions to the classical hematopoietic system have expanded our understanding by introducing the concept of common monocyte progenitors (CMoPs) during MDP differentiation. CMoPs, in turn, undergo differentiation into monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells. Conversely, CLPs, originating from HSCs, are capable of differentiating into a spectrum of lymphoid lineages, encompassing B cells, T cells, and natural killer T cells. This comprehensive framework outlines the intricate process of hematopoiesis, illustrating the diverse range of cell types generated from HSCs and their respective lineage trajectories [53]. (Fig. 2A).Fig. 2 (A) The Atlas of Immune Cell Differentiation serves as a comprehensive guide to the diverse developmental pathways of immune cells. (B) Certain CC chemokines selectively bind to their corresponding receptors, orchestrating the chemotaxis of immune cells towards the pulmonary tissue, thereby intensifying the progression of PH. (C) A horizontal schematic elucidates the interplay between chemokines and their receptors, effectively recruiting immune cells to foster an inflammatory milieu within the pulmonary system. (D) The pharmacological inhibition of CC chemokines effectively retards both the inflammatory processes and the advancement of pulmonary hypertension.

Fig. 3 CC chemokines and their corresponding receptors intricately participate in signaling pathways that are intimately associated with PH processes.

In an experimental study examining the effects of hypoxia-induced PH, notable alterations in myeloid cell subpopulations and their associated pathogenic effects were observed. Specifically, Yu YA et al. documented a significant increase in interstitial macrophages (IMØ) induced by hypoxia within the lungs of PH-afflicted mice, in contrast to their normoxic counterparts. This observation suggests that these IMØ populations in the lungs predominantly originated from Ly6Clo non-classical monocytes. This discovery lends further support to the notion that non-classical monocytes and macrophages infiltrate the pulmonary vasculature, consequently promoting vascular remodeling and the subsequent development of PH [46]. These findings were further substantiated by the study conducted by Florentin J et al. In both individuals afflicted by PH and hypoxia-exposed mice, a heightened production and elevated levels of various chemokines and cytokines, including CCL2, IL-1β, IL6, and IL-18, were detected within the pulmonary tissue. Utilizing fluorescence-activated cell sorting, the researchers successfully isolated circulating monocytes from the blood of pH patients and demonstrated an augmented expression of corresponding chemokine receptors, specifically CCR1, CCR2, and CCR5 in these monocytes. However, in a significant observation, mice deficient in CCR2 exposed to chronic hypoxia exhibited notably reduced levels of lung inflammation and remodeling in comparison to their wild-type counterparts. Additionally, the inhibition of chemokine expression resulted in a diminished recruitment of infiltrating monocytes into the lung, accompanied by a concurrent attenuation of pulmonary artery wall remodeling [54].

Monocytes and macrophages play indispensable roles in the immune response associated with PH. Monocytes, belonging to the category of leukocytes, are a subset of immune cells, and they, along with macrophages and dendritic cells, collectively constitute the mononuclear system of phagocytes [55]. Human monocytes can be categorized into three distinct subpopulations based on their surface marker expression profiles. These subpopulations include the “classical” monocytes (CD14++, CD16-), formerly characterized as inflammatory monocytes, the “non-classical” monocytes (CD14+, CD16++), often referred to as patrol monocytes, and an intermediate subpopulation (CD14++, CD16+) that is found within both of the aforementioned subsets [55]. Inflammatory monocytes are mobilized and recruited to localized sites of inflammation, where they subsequently undergo differentiation into either macrophages or dendritic cells [55]. Macrophages, a prominent subset of leukocytes widely distributed across various tissues, assume critical functions in preserving immune homeostasis, orchestrating inflammatory responses, and governing the development and functionality of organs [56]. Contrary to the traditional assumption that tissue macrophages primarily originate from circulating monocytes, it has been revealed that several tissue macrophage populations are, in fact, derived from the yolk sac or fetal liver during the early stages of embryonic development. This unique origin is particularly evident in tissues such as the heart and lungs, shedding light on the distinctive developmental pathways of tissue-resident macrophages in these specific organs [56]. Macrophage subsets are subject to further categorization, with M1 macrophages associated with proinflammatory helper T lymphocyte Th1-type responses, and M2 macrophages linked to helper T lymphocyte Th2-type responses [56].

The upregulated expression of CC chemokines resulting from the interplay between monocytes/macrophages and the endothelium assumes a pivotal role in the immune responses associated with PH. To illustrate, in a study conducted by Mercier O et al., which aimed to elucidate the involvement of PAECs in vascular remodeling within the context of CTEPH, elevated levels of CCL2 and other inflammatory cytokines were identified in PASMCs and PAECs derived from CTEPH patients. Notably, CCL2, which exhibited a significant increase in patient samples, occupies a central role in the recruitment of monocytes to thrombi and vessel walls. This chemotactic effect of CCL2 contributes substantially to the process of vascular remodeling in PH. These findings underscore the significance of CC chemokines, particularly CCL2, in mediating the immune responses and pathological changes characterizing PH [57]. In individuals diagnosed with PAH, macrophage activation, a key contributor to pulmonary vascular inflammation, plays a significant role in the progression towards right ventricular failure. A study conducted by Al-Qazazi R et al. unveiled a pronounced increase in the abundance of macrophages within the right ventricle of the MCT rat model, as compared to the right ventricle of healthy control rats. Notably, elevated levels of CCR2, a chemokine receptor closely associated with macrophages of monocyte origin, were detected in the right ventricle of both the MCT-induced and Sugen hypoxic (SuHx) rat models of PAH. Furthermore, these macrophages exhibited heightened expression levels of proinflammatory markers characteristic of the M1 phenotype, indicating their active participation in the inflammatory response. Of particular note, in both PAH models, more than 50 % of the cells within the right ventricle expressing CCR2 were identified as macrophages, further underscoring their integral role in the disease-related inflammation processes. These findings collectively emphasize the substantial involvement of macrophages and CCR2-expressing cells in the right ventricular inflammation associated with PAH [58]. These findings underscore the significant role played by CC chemokines and their corresponding receptors, orchestrated through monocytes/ macrophages, in the pathogenesis of PH. The intricate interplay between these immune cells and the pulmonary vasculature contributes substantially to processes such as vascular remodeling, inflammation, and the onset of right ventricular dysfunction. These observations underscore the potential of CC chemokines and their receptors as promising therapeutic targets for the management and treatment of PH.

Lymphocytes and CC chemokines in PH

Secondary lymphoid organs (SLOs) are strategically positioned along lymphatic vessels, serving as pivotal hubs for immune cell attraction and lymphocyte homeostasis. Within SLOs, tissue cells express chemokines, including CCL19 and CCL21, which are responsible for attracting cells expressing the chemokine receptor CCR7. Additionally, CCL20 functions to recruit cells expressing CCR6. This orchestrated chemokine signaling within SLOs plays a crucial role in the recruitment and regulation of immune cell populations within lymph nodes [59]. Naive lymphocytes maintain a dynamic equilibrium through their continuous circulation between the bloodstream and secondary lymphoid organs. This finely tuned process is underpinned by the essential role of chemokine signaling in preserving lymphocyte homeostasis [59]. Innate lymphoid-like cells (ILCs) serve as innate counterparts to T lymphocytes and are distinguished by their lack of adaptive antigen receptors generated through genetic recombination [60]. ILCs comprise distinct subpopulations, including ILC1s, ILC2s, ILC3s, and natural killer (NK) cells. Functionally, ILC1s, ILC2s, and ILC3s exhibit analogous roles to CD4 T helper (Th) cells, specifically resembling Th1, Th2, and Th17 cells, respectively. Conversely, NK cells fulfill functions akin to those of CD8 cytotoxic T cells [60]. These innate immune cells participate in immune responses and contribute to immune regulation and tissue homeostasis.

Following stimulation by cytokines, primary T cells undergo differentiation into specific subsets, encompassing helper T cells, cytotoxic T cells, and regulatory T cells, each of which serves distinct functions in the context of disease [61]. Van Uden D conducted a study that specifically investigated the elevated presence of T cells and chemokines within vascular lesions in patients diagnosed with CTEPH. The study revealed a significant increase in the population of naive CD4 and CD8 T cells, along with a subset of regulatory T cells, notably the Th17-associated CCR6 T cells, in the characterization of peripheral blood T cells when compared to a control group of healthy individuals. Additionally, the study established a correlation between the aberrant phenotype of circulating T cells in CTEPH patients and the levels of cytokines and chemokines in their plasma [62]. Perros et al. conducted a study involving patients with IPAH and observed a similar upregulation of CD8 + T cells, alongside increased expression of inflammatory mediators, including CCL2/CCR2, CCL5/CCR5/CCR1. These results provided additional support for the previously mentioned findings [63]. Cytotoxic T cells, known for their potent cytolytic activity, play a role in promoting inflammation and contributing to PH [64]. A bioinformatics analysis investigating potential biomarkers and immune infiltration features in PAH revealed a significant upregulation of CD8 + T cells, concomitant with the presence of inflammatory mediators, including CCL2/CCR2, CCL5/CCR5/CCR1 [65]. Conversely, regulatory T cells are critical in inhibiting the progression of pH by modulating target T cells and antigen-presenting cells, suppressing cell proliferation, mitigating pulmonary vascular wall inflammation, and inhibiting pulmonary artery remodeling [61]. In a mouse model of hypoxia-induced PAH, the importance of regulatory T cells in maintaining immune homeostasis during disease was demonstrated by their ability to improve hypoxia-induced PAH and vascular remodeling. Additionally, regulatory T cells were shown to upregulate anti-inflammatory factors and downregulate pro-inflammatory cytokines, such as CCL2 [66].

After developing and maturing in SLOs, B cells enter circulation and play a crucial role in the humoral immune response. A study conducted by Qi D et al., investigating the role of HIF1α in vascular remodeling, demonstrated that HIF1α deficiency in vascular smooth muscle cells significantly inhibited the expression of CCL7 and the infiltration of CD45-positive cells [67]. In a clinical trial conducted by Zamanian RT et al. involving patients with systemic sclerosis-associated PAH, the potential therapeutic effect of B-cell depletion was confirmed. The results of this trial primarily attributed the observed benefits to a reduction in the number of B cells, implicating their involvement in disease progression [68].

NK cells play a crucial role in identifying abnormal cells, and their loss of function is a characteristic feature of PH, contributing to vascular remodeling in animal models of the disease. NK cells are essential for eliminating infections, malignancies, and mediating cytotoxicity in immune cells. They also express pro-inflammatory factors, including chemokines such as CCL3, CCL4, and CCL5, making them pivotal in controlling inflammation, autoimmune responses, and maintaining overall body homeostasis [69] NK cells can be broadly categorized into two subtypes: CD56bright and CD56dim. Pulmonary NK cells are thought to exhibit lower cytotoxicity compared to their blood counterparts, suggesting more stringent immune modulation in the lungs [70]. In an experiment focusing on immune cell-induced lung injury, the expression levels of interferon-γ, CCL2, CCL3, and CCL5 produced by NK cells progressively increased and contributed to the recruitment of inflammatory cells, thereby promoting disease progression [71].

Dendritic cells and CC chemokines in PH

DCs represent a diverse group of antigen-presenting cells, including conventional DCs (cDCs), monocyte-derived DCs (moDCs), plasmacytoid DCs (pDCs), and Langerhans cells, all of which play critical roles in regulating and balancing lung inflammation and immunity by migrating to specific locations. The migratory behavior of DCs is primarily governed by chemokine interactions with their corresponding chemokine receptors [72]. Initially, immature cDCs, produced by CDPs, serve as immune response sentinels. Upon activation by PAMPs or other stimuli, immature cDCs upregulate CCR7 expression. This interaction between CCR7 and its ligand CCL21, found on lymphatic endothelial cells, facilitates DC migration into the initial lymphatic lumen. Subsequently, CCR7 is once again instrumental in guiding DCs into the lymph node parenchyma [73]. While most DC precursors exit the bone marrow and enter the circulation to migrate to lymphatic and non-lymphoid tissues, specific DC subpopulations reside within lymph nodes, where they activate T and B cells in response to encounters with pathogens [74].

In a study conducted by van Uden D et al., Tnfaip3DNGR1-KO mice were observed to develop a spontaneous model of pH due to the deletion of the A20 protein in the NF-κB signaling pathway, which is regulated by cDCs. These mice exhibited an increased number of myocardial dendritic cell infiltrates in the right ventricle, particularly in the lungs. Additionally, both Tnfaip3DNGR1-KO mice and IPAH patients showed the presence of dendritic cells and CD8 + T cells in close proximity in the perivascular and parenchymal areas, suggesting a potential relevance of cDC1s in the pathology of PAH. Furthermore, infiltration of mid-CD11c + dendritic cells, CD19 + B cells, and CD3 + T cells was observed in the right cardiac ventricle of the mice [75]. Koudstaal T and colleagues demonstrated that dendritic cell subpopulations in the lungs of Tnfaip3DNGR1-KO mice tend to cluster together. These cells can produce cytokines upon activation by T cells, promoting inflammation, and secrete pathogenic antibodies when interacting with B cells. Lung biopsies from IPAH patients showed an accumulation of dendritic cells in remodeled pulmonary vessels, while their presence in the blood was decreased. These dendritic cells were predominantly located in tertiary lymphoid organs (TLOs) and pulmonary lymph nodes near small pulmonary arteries. TLOs are often considered indicators of persistent inflammation and have been suggested to play a role in PH progression [76]. Perros F et al. investigated the therapeutic effect of perivascular TLOs in the lungs of IPAH patients and found significantly elevated mRNA levels of chemokines CCL19, CCL20, and CCL21 compared to controls. The increased expression of these chemokines attracted dendritic cells expressing their corresponding receptors CCR6 and CCR7. During inflammation, Ly6C + hi monocytes in the blood are recruited to the lungs via CCR2 and differentiate into moDCs. These cells then interact with different subsets of Th cells, including Th1 or Th2, to stimulate immune responses. Immune activation and inflammation in the lungs may contribute to the development of PH. Hautefort A et al. found that in PAH patients, moDCs accumulated more in the lungs compared to controls. Additionally, these cells activated and stimulated the proliferation of CD4 + T cells, leading to a decrease in Th2 responses and an enhanced Th17 immune profile. Notably, dendritic cells showed a higher tendency to migrate toward the T-cell area in lymphoid tissues compared to controls, possibly driven by chemotactic gradients of CCL19 and CCL21 [77].

Mast cells and CC chemokines in PH

Mast cells play a pivotal role in allergic responses, serving as essential contributors to the rapid release of mediators. They function as important sentinels of the innate immune response, possessing the capability to recognize and respond to a diverse range of stimuli through the expression of various receptors. These receptors encompass Receptor I for the Fc region of immunoglobulin E (FcεRI), GPCRs, TLRs, NOD-like receptors, and non-immunoglobulinase receptors. This extensive repertoire of receptors enables mast cells to detect and react to not only infectious agents but also endogenous molecules released from damaged or inflamed tissues [78]. For instance, when FcεRI receptors on mast cells engage with their ligands, the cells undergo degranulation, leading to the release of histamine and proteases. In addition to degranulation, mast cells actively participate in lipid-derived pathways, resulting in the rapid release of inflammatory mediators, such as prostaglandin D2, leukotriene C4, and platelet- activating factor. Furthermore, mast cells are capable of synthesizing and secreting cytokines and chemokines, a process regulated at the transcriptional level [78].

Histopathological examinations of both PAH patients and animal models of pH have consistently revealed the accumulation and activation of mast cells in the pulmonary perivascular region [79]. Moreover, studies involving the administration of mast cell degranulation blockers and histamine antagonists have shown a concurrent decrease in vascular endothelial growth factor levels and circulating proangiogenic CD34 + CD133 + progenitor cells. These findings suggest that mast cells may play a role in the vascular remodeling associated with PH [80]. In a study by Kubo F et al., Adgrf5-deficient mice exhibited enhanced mast cell accumulation and an upregulation of CCL2 expression in lung endothelial cells, which contributed to inflammation [81]. Additionally, mRNA analysis of chemotactic receptors on mast cells revealed a notable upregulation of CCR1 and CCR5 in human bone marrow and peripheral blood mast cells, while mast cells in the lung displayed lower expression of CCR5 [82].

Eosinophils/Basophils and CC chemokines in PH

Eosinophils and basophils, which share certain characteristics with mast cells, originate from CMPs and express the FcεRI on their cell surface, a receptor that regulates immune responses and the release of effector mediators [83]. These cells are activated by PAMPs during lung inflammation and serve as a primary line of defense against invading microorganisms. Eosinophils and basophils exhibit cytotoxicity and possess important immunomodulatory properties, producing a wide range of cytokines, chemokines, and other proinflammatory factors [84]. Investigations into eosinophil infiltration and chemotaxis in peripheral blood and lung tissues of patients with PAH and in mouse models of SuHx-induced PH have shown a low percentage of eosinophils in the periphery but a higher level of infiltration in the lung tissues. Additionally, elevated expression of eosinophil-associated chemokines, including CCL11, CCL24, and CCL26, has been detected in lung tissue [85]. Experimental studies by Motomura Y et al. have demonstrated the crucial role of eosinophils in inflammation. Specifically, eosinophil-derived interleukin-4 was found to be responsible for the activation of innate lymphocytes in the lung in a mouse model lacking 3′UTR. Subsequently, an increase in the expression of inflammatory cytokines and chemokines, including CCL11, CCL5, and CCL3, was observed. Additionally, induction with papain led to an elevated number of activated CD11c eosinophils, accompanied by the upregulation of inflammatory cytokines and chemokines such as IL-6, interleukin-13, CCL7, and CCL11 [86].

Chemokine regulation of PH-associated inflammatory signaling pathways

The role of NF-κB signaling pathway in PH.

The NF-κB signaling pathway, encompassing both canonical and non-canonical pathways, assumes a central role in the physiological and pathological processes of PH. These pathways entail distinct mechanisms of activation, wherein plasma membrane-bound PRRs in innate immune cells serve as pivotal components for the identification of pathogens and tissue damage. Upon recognition, these receptors instigate the upregulation of pro-inflammatory factors, triggering an inflammatory response aimed at pathogen elimination and tissue restoration. Activation of the canonical NF-κB pathway in the innate immune response is primarily governed by plasma membrane-bound TLRs or members of the TNF receptor family. A critical step in this pathway involves the signal-induced phosphorylation of IκB molecules by the IKK complex, comprising IKKα, IKKβ, and IKKγ subunits [87]. Under normal conditions, NF-κB dimers, predominantly p50/p65, are sequestered in the cytoplasm by IκB. Activation of the canonical pathway leads to IKK-mediated phosphorylation of IκBα, liberating p50/p65 dimers that translocate to the nucleus to initiate transcriptional activity [88]. Conversely, the non-canonical NF-κB pathway involves the translocation of RelB/p52 heterodimers into the nucleus, representing a crucial step in this pathway. CD40 receptors activate NF-κB-inducing kinase (NIK), which in turn phosphorylates NIK, releasing RelB/p52 and facilitating their nuclear translocation [88]. The expression of inflammatory mediators, including IL-18, IL-1β, and CC chemokines like CCL2 and CCL5, released upon the activation of the NF-κB signaling pathway, promotes the development of immune-inflammatory mechanisms and pulmonary artery remodeling [34]. Consequently, pro-inflammatory mediators and CC chemokines further stimulate the NF-κB signaling pathway and contribute to the progression of PH [35]. Extensive research has underscored the pivotal role of the NF-κB pathway in initiating the inflammatory response and fostering cell proliferation in PH [89]. Inhibition of the NF-κB pathway has demonstrated therapeutic efficacy in PH. Notably, there exists crosstalk between the NF-κB pathway and other signaling pathways within this process [90]. For instance, in hypoxic PH models, the activation of the Akt/mTOR signaling pathway augments the proliferation of PASMCs and pulmonary artery remodeling. This phenomenon is concomitant with increased expression of phosphorylated NF-κB (p65) in both PH models and lung tissues from patients, suggesting that mTORC1 operates upstream of NF-κB activation, and crosstalk occurs between these two signaling pathways. Furthermore, the NF-κB signaling pathway exhibits crosstalk with other signaling pathways in PH, such as the mitogen-activated protein kinase (MAPK) signaling pathway and adenosine monophosphate-activated protein kinase signaling pathway [91], [92].

The role of JAK/STAT signaling pathway in PH.

The Janus kinase/signal transduction and activator of transcription (JAK/STAT) signaling pathway is a pivotal cellular pathway responsible for regulating various cellular functions, including cell proliferation, differentiation, and immune responses [93]. Activation of the JAK/STAT pathway is initiated by the transphosphorylation of JAK proteins, triggered by the interaction between extracellular ligands and their corresponding cell surface receptors. This interaction leads to the phosphorylation of specific intracellular tyrosine residues, serving as docking sites for STAT proteins. Subsequently, the phosphorylated STAT proteins form homodimers or heterodimers. In the context of PH, the activation of the JAK/STAT pathway is instigated by intracellular ligands binding to their respective receptors. Following tyrosine residue phosphorylation, STAT proteins associate with receptors to create dimers. These activated STAT dimers translocate to the nucleus, where they initiate the transcription of target genes [93], [94].

The excessive activation of the inflammatory response in individuals with PH culminates in heightened proliferation and differentiation of lung cells. This phenomenon is orchestrated by various inflammatory mediators and facilitated by the dysregulation of the JAK/STAT signaling pathway. In a comprehensive study conducted by Yerabolu and colleagues focusing on PH, interventions targeting the JAK/STAT signal transduction pathway demonstrated notable enhancements in cardiopulmonary function and a reduction in pulmonary vascular remodeling among patients with PH [95]. Furthermore, in pulmonary vascular diseases such as pulmonary embolism and fibrosis, the JAK/STAT signaling pathway mitigates the expression levels of inflammatory mediators and chemokines, specifically CCL3, CCL4, CCL5, CCL13, and CCL20, consequently alleviating lung injury [96]. These compelling findings signify that the manipulation of the JAK/STAT pathway presents a promising therapeutic approach for ameliorating the pathological processes associated with PH.

The role of MAPK signaling pathway in PH.

The MAPK signaling pathway serves as a crucial intracellular cascade that responds to diverse extracellular stimuli. This pathway involves three enzymes: mitogen-activated protein kinase kinase kinase, mitogen-activated protein kinase kinase, and MAPK. In mammals, MAPK encompasses c-Jun NH2-terminal kinase (JNK), P38 MAPK, extracellular signal-regulated kinase (ERK), and ERK5, each exhibiting distinct structural and regulatory characteristics [97]. Activation of this pathway is typically initiated by the binding of ligands to receptor tyrosine kinases (RTK), triggering RTK dimerization, activation, and autophosphorylation. Subsequently, the recruitment and activation of raf protein kinase (RAF) kickstart a three-phase phosphorylation cascade culminating in the phosphorylation of mitogen-activated protein kinase by RAF and the subsequent activation of ERK. The phosphorylated ERK translocates to the nucleus [98]. Furthermore, the activation of kinase 1 contributes to the activation of P38 and JNK in response to external stimuli [99]. The involvement of the MAPK signaling pathway in PH is discernible in both experimental hypoxic PH models and PH patients, where enhanced expression of ERK, JNK, and P38 has been detected in pulmonary tissues. Notably, hypoxia-induced elevation of Notch4 expression has also been documented, with its interaction with the MAPK pathway confirmed through immunoprecipitation assays, thereby promoting the proliferation and migration of activated PASMCs [100]. Ultimately, activation of the MAPK signaling pathway culminates in the activation of the transcription factor activator protein-1 (AP-1), a dimeric transcription factor regulating the expression of multiple cytokines and chemokines involved in immune responses [100]. Both experimental investigations and patient studies have affirmed the role of the MAPK signaling pathway in mediating PH, with an upregulation of ERK, JNK, and P38 expression noted in lung tissues [101], [102]. In a rat model of acute pulmonary thromboembolism-induced PH with acute lung injury, Chun et al. reported a close association between MAPK activation and CC chemokines [103]. Additionally, the induction of Notch4 expression under hypoxia and its interplay with the MAPK pathway have been demonstrated through immunoprecipitation assays, fostering the proliferation and migration of activated PASMCs [104].

The role of Notch signaling pathway in PH.

GPCRs play a crucial role in mediating the canonical Notch pathway, which is essential for the development and maintenance of various tissues and organs in the human body [105]. Dysregulated Notch signaling can lead to severe vascular defects. One specific mediator, Notch3, has been implicated in the exacerbation of pH and vascular remodeling. Notch3 is predominantly expressed in pulmonary vascular smooth muscle cells, particularly in small pulmonary arteries [106]. Inhibiting Notch3 signaling has been shown to slow down the post-signaling proliferation of pulmonary vascular smooth muscle cells. Similarly, targeting Notch1 signaling has been found to slow down pulmonary endothelial cell proliferation and reduce immune cell infiltration in the pulmonary vascular wall. Therefore, selectively targeting the Notch pathway holds promise as a safe and effective strategy for treating PH [107]. While there is limited literature supporting the role of CC chemokine deficiency and the Notch pathway in PH development, a study by Yu YR et al. revealed a potential interaction between the CCL2/CCR2 signaling axis and the Notch pathway [44]. Both CCR2 and Notch3 are secreted by pulmonary vascular smooth muscle cells, suggesting that these cells may directly regulate the Notch pathway. Alternatively, CCR2 might mediate other signaling pathways that indirectly influence the Notch pathway. However, it is essential to note that further evidence is required to fully understand and support this conclusion.

CC chemokines as potential therapeutic targets: Opportunities and challenges

Opportunity: the importance of CC chemokines.

The pathophysiology of pH is primarily characterized by progressive vascular remodeling in the pulmonary arteries and small arterioles, resulting in hypoxia, heart failure, and ultimately, patient mortality [108], [109]. Multiple mechanisms drive this pathological vascular remodeling, including genetic mutations, epigenetic modifications, inflammatory responses, endothelial dysfunction, oxidative stress, and extracellular matrix remodeling. Importantly, these mechanisms often intersect with the immune-inflammatory response, further complicating the development of PH. In the pulmonary vasculature of pH patients, an inflammatory microenvironment prevails, characterized by increased expression of pro-inflammatory cytokines and chemokines. Some cytokines, such as IL-6, directly influence the proliferation and migration of pulmonary endothelial and smooth muscle cells, while chemokines play a pivotal role in modulating immune cells, thus promoting pulmonary vascular remodeling. Notably, chemokine-deficient mice spontaneously develop PH, underscoring the significant impact of these molecules on disease progression. This paper focuses on the specific effects of CC chemokines and their corresponding receptors on pulmonary vascular remodeling and PH, particularly within various immune cell types including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, mast cells, eosinophils, and basophils. CC chemokines and their receptors actively recruit these immune cells to accumulate within the lung, fostering an inflammatory response that exacerbates the proliferation and migration of pulmonary endothelial and smooth muscle cells, ultimately contributing to vascular remodeling and PH. Therefore, given the close association of pH with the immune-inflammatory response, targeting CC chemokines and their receptors holds substantial therapeutic promise and may offer a potential avenue for reversing adverse vascular remodeling.

Challenge: CC chemokine deficiency.

Three pathways are currently recognized for the treatment of PH: the nitric oxide pathway, the prostaglandin pathway, and the endothelin pathway [108]. While these therapeutic agents mainly focus on inducing vasoconstriction or vasodilation, they have significant limitations, including a lack of lung targeting, drug tolerance, low bioavailability, and severe side effects. Therefore, the search for potent, safe, and effective drugs for PH treatment remains a primary goal. Immunosuppressive agents have emerged as promising candidates for addressing the immunoinflammatory responses that exacerbate PH development. IL-1 blockade has also emerged as a promising therapeutic target for preventing PH progression, with the IL-1 receptor antagonist (IL-1Ra, anakinra) exhibiting excellent blocking efficacy in animal models [6]. IL-1Ra's effectiveness in treating PAH in mice has been attributed to its impact on macrophage-expressed endothelin-1 and its ability to target CCL2, reducing CCL2 and inflammatory expression levels [6]. IL-1Ra blocks the interleukin-1 receptor 1/MyD88/NF-κB signaling pathway in pulmonary arteries, leading to reduced levels of perivascular pro-inflammatory cytokines and macrophage expression [110]. The aryl hydrocarbon receptor (AHR) has also garnered attention for its role in hypoxia-induced PH models, where it recruits T cells and macrophages to the pulmonary vasculature and promotes the upregulation of inflammation-associated signaling pathways, pro-inflammatory cytokines, and CC chemokines. These pathways include NF-κB signaling, TNF signaling, Toll-like receptor signaling, as well as the production of IL-6, IL-13, CCL7, CCL19, CCR1, among others. Consequently, AHR antagonists are emerging as promising agents for PH treatment [111].

While the drugs mentioned earlier primarily target immune cells to slow the development of PH, there has been limited research on drugs that directly address CC chemokines and their receptors (Fig. 2D). Interestingly, certain plant compounds have shown promise in inhibiting CC chemokines and their receptor-mediated immune-inflammatory responses, thereby slowing the progression of PH. One such compound is betaine, which has demonstrated its ability to attenuate inflammatory responses induced by MCT in a PAH model. Betaine's mechanism of action primarily involves the inhibition of the CCL2-regulated NF-κB pathway. This inhibition results in decreased expression levels of key inflammatory mediators, including TNF-α, IL-1β, and CCL2 [26]. CCL2 has been implicated in the context of acute pulmonary thromboembolism-induced PH, and the administration of resveratrol, a natural compound found in certain plants, has been shown to down-regulate CCL2 expression and inhibit the activation of p38 mitogen-activated protein kinase (p-p38 MAPK). This inhibition contributes to the deceleration of the PH process [103]. Saffron is another natural compound that has demonstrated the ability to inhibit disease progression in a rat model of PAH induced by MCT. Saffron's mechanism of action involves the suppression of the CCL2/CCR2 signaling axis, thereby attenuating disease progression. This attenuation is primarily characterized by a reduction in collagen fiber deposition, a decrease in right ventricular hypertrophy, and the suppression of CCL2/CCR2 expression levels along with pro- inflammatory cytokines [5]. All the aforementioned experimental results bolster the potential of targeting CC chemokines and their receptors as a treatment option for PH. The techniques employed in the experiments comprised hematoxylin-eosin staining, immunoprotein blotting, immunohistochemistry, immunofluorescence, and real-time fluorescence quantitative PCR.

While certain drugs have been identified and have demonstrated therapeutic potential in targeting CC chemokines and their receptors to modulate immune cells and mitigate the progression of PH, there are notable limitations associated with these approaches. These limitations include issues such as low bioavailability, uncertainty regarding toxicity, and a lack of comprehensive pharmacokinetic, pharmacometabolic, and clinical studies (Table 1).Table 1 Current animal models interest in CC chemokines for the treatment of PH.

Therapeutic medicine	Model	Target and Pathway	Reference	
Receptor antagonists	animal models	Reduced expression levels of CCL2 and pro-inflammatory factors	[6], [110]	
AHR antagonist	Hypoxia-induced model	Reduced expression levels of CC chemokines and pro-inflammatory factors	[111]	
Betaine	MCT model	Inhibition of the CCL2-regulated NF-κB pathway	[26]	
Resveratrol	Acute pulmonary thromboembolism-induced PH in rats	Down-regulate CCL2 expression and inhibit p-p38 MAPK pathway	[103]	
Saffron	MCT model	suppression of CCL2/CCR2 expression levels along with proinflammatory cytokines	[5]	

Prospects and perspectives: immunotherapy combined with drug delivery systems.

The therapeutic potential of immunotherapy in PH has been extensively studied and documented, although its effectiveness is often constrained by various factors, including high efficacy but limited stability. There is a growing interest in exploring innovative drug delivery systems that combine plant monomers, antagonists, and traditional medications. Utilizing novel drug carriers such as liposomes, polymer nanodots, tungsten-based polymetallic oxide nanodots, protein carriers, and hydrogels for drug delivery holds significant promise [112].

Currently, among the novel drug delivery systems under investigation for the treatment of PH, liposomes and polymeric nanoparticles are the most commonly studied. Combining liposomes and polymeric nanodots with sildenafil for drug delivery offers several advantages, including enhanced bioavailability, improved biocompatibility, enhanced targeting, and mitigation of sildenafil's toxicities, such as the unwanted accumulation of the drug in small pulmonary arteries [113], [114]. Notably, the tungsten-based polymetallic oxonate nanodots, as researched by Liu H et al., have emerged as promising antioxidant nanotherapeutics for potential PH treatment [108]. These nanodot materials offer several advantages as novel drug delivery systems for PH: firstly, they enhance bioavailability while minimizing toxic side effects; secondly, they can inhibit relevant signaling pathways or pathogenic mechanisms involved in PH development, such as the Notch signaling pathway, oxidative stress, and inflammation. Thirdly, they exhibit a high degree of pulmonary targeting [108]. Furthermore, hydrogels have also demonstrated the ability to slow down PH progression, primarily by counteracting vascular remodeling induced by the fibrosis of exogenous fibroblasts in the pulmonary arteries [115]. Consequently, the exploration of combined drug delivery systems with traditional medications holds great promise for effectively reversing the pathogenesis of PH.

Conclusion and future directions

The pivotal role of chemokines and their corresponding receptors in regulating immune cells in PH patients is of paramount importance and has been closely associated with disease severity and prognosis. Initially, chemokines were primarily acknowledged for their crucial role as chemotactic agents involved in recruiting innate immune cells and facilitating acute inflammatory responses. However, it has become increasingly evident that the chemokine system also plays critical roles in immune cell trafficking, migratory behavior, cellular localization, and intercellular interactions. Among the various chemokine families, CC chemokines have garnered significant attention in the context of pH pathobiology, as they contribute to the initiation of inflammatory and immune responses. These chemokines participate in a spectrum of cellular processes that are specific to the remodeling observed in PH, including the stimulation of proliferation, migration, and the release of inflammatory cytokines in endothelial cells, smooth muscle cells, and fibroblasts. Moreover, an upregulation of chemokines and cytokines has been consistently observed in the lung tissue of pH models induced by various factors. These findings underscore the profound significance of the chemokine system in the pathogenesis of pH and emphasize its potential as a viable therapeutic target.

Despite the promising outcomes derived from preclinical investigations regarding the potential advantages of inhibiting chemokines and their receptors in the management of PH, clinical therapeutic interventions aimed at these molecular targets are currently lacking. In animal models of PH, pharmacological agents designed to target chemokine receptors have demonstrated efficacy in either preventing or reversing the disease [5], [6], [26], [103], [111]. Nevertheless, despite the encouraging results emerging from numerous animal studies centered on chemokines, these findings have not yet translated into practical therapeutic solutions for PH in clinical practice [5], [6], [26]. Hence, there exists a pressing need for further investigation into chemokines as potential targets for PH treatment, as they hold the potential to serve as innovative therapeutic strategies and tools for the clinical management of this disease.

Compliance with ethics requirements

This article does not contain any studies with human or animal subjects.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Qian Yan, Master of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: 731404655@qq.com. In this review, the immune response and inflammation in pulmonary hypertension (PH) have been systematically summarized based on recent studies. The relationship between CC chemokines and the pathogenesis of PH is summarized in clinical and animal models. We found that although the immune response serves as an important potential factor in the pathogenesis of PH, less attention has been paid to CC chemokines and their receptors. We believe that a greater understanding of the relationship between PH and CC chemokines and their receptors is a pressing issue. We believe that we need to further clarify the pathogenesis of PH and provide basis for the clinical treatment of PH.

Shasha Liu, Department of Pharmacy, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China. Email: 10188498@qq.com

Yang Sun, Doctor of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. No. 300, Xueshi Road, Hanpu Science and Education Park, Yuelu District, Changsha City, Hunan Province. Email: 15846570429@163.com

Chen Chen, Doctor of pharmacy, Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China. Email: ery_chenc@lzu.edu.cn

Yantao Yang, Professor of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: xdyyt1@163.com

Songwei Yang, Doctor of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: 15200832653@163.com

Meiyu Lin, Doctor of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: 258486371@qq.com

Junpeng Long, Master of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: 2297651182@qq.com

Yuting Lin, Master of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: 1034296969@qq.com

Jinping Liang, Master of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: 2086704301@qq.com

*Corresponding author, Qidi Ai, Doctor of pharmacy, Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces & College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China. Email: 278339420@qq.com

*Corresponding author, Naihong Chen, Professor of pharmacy, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Email: chennh@imm.ac.cn

Acknowledgments

This study was supported by National Natural Science Foundation (Grant No. U2202214), the Outstanding youth project of Hunan Education Department (Grant No. 21B0354), Changsha Natural Science Foundation (Grant Nos. kq2202269 and kq2014091), Hunan Natural Science Foundation (Grant Nos. 2021JJ30512, 2022JJ40313, 2022JJ40456, 2023JJ60126 and 2023JJ60471), Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine (Grant No. B2023061), Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd.(Grant No. 212010), Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund (Grant Nos. 2019xjjj001 and 2021XJJJ028), Hunan University of Chinese Medicine discipline construction project (22JBZ052), Innovation project of Hunan University of Traditional Chinese Medicine (2022CX12), Key Project of Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University (202329-2), Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica, The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine, The key discipline of biological engineering of Hunan University of Chinese medicine [2018] No.3 and Pharmaceutical Open Fund of Domestic First-class Disciplines (cultivation) of Hunan Province.
==== Refs
References

1 Poch D. Mandel J. Pulmonary hypertension Ann Intern Med 174 2021 Itc49 Itc64 33844574
2 Walter K. Pulmonary hypertension Jama 326 2021 1116 34546299
3 Sockrider M. What Is pulmonary hypertension? Am J Respir Crit Care Med 203 2021 P12 P13 33646084
4 Smolders V. Lodder K. Rodríguez C. Tura-Ceide O. Barberà J.A. Jukema J.W. The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression Cells 2021 10 35011571
5 Sheng Y. Gong X. Zhao J. Liu Y. Yuan Y. Effects of Crocin on CCL2/CCR2 Inflammatory Pathway in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats Am J Chin Med 50 2022 241 259 34931588
6 Bui C.B. Kolodziej M. Lamanna E. Elgass K. Sehgal A. Rudloff I. Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension Front Immunol 10 2019 1480 31354700
7 Itoh T. Nagaya N. Ishibashi-Ueda H. Kyotani S. Oya H. Sakamaki F. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension Respirology 11 2006 158 163 16548900
8 Nie X. Tan J. Dai Y. Liu Y. Zou J. Sun J. CCL5 deficiency rescues pulmonary vascular dysfunction, and reverses pulmonary hypertension via caveolin-1-dependent BMPR2 activation J Mol Cell Cardiol 116 2018 41 56 29374556
9 Hoffmann-Vold A.M. Hesselstrand R. Fretheim H. Ueland T. Andreassen A.K. Brunborg C. CCL21 as a Potential Serum Biomarker for Pulmonary Arterial Hypertension in Systemic Sclerosis Arthritis Rheumatol 70 2018 1644 1653 29687634
10 Kologrivova I. Shtatolkina M. Suslova T. Ryabov V. Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of Inflammation and Repair After Myocardial Infarction Front Immunol 12 2021 664457
11 Oliveira A.C. Richards E.M. Raizada M.K. Pulmonary hypertension: Pathophysiology beyond the lung Pharmacol Res 151 2020 104518
12 Zhong Y. Yu P.B. Decoding the Link Between Inflammation and Pulmonary Arterial Hypertension Circulation 146 2022 1023 1105 36154621
13 Hu Y. Chi L. Kuebler W.M. Goldenberg N.M. Perivascular Inflammation in Pulmonary Arterial Hypertension Cells 2020 9 33375150
14 Wang R.R. Yuan T.Y. Wang J.M. Chen Y.C. Zhao J.L. Li M.T. Immunity and inflammation in pulmonary arterial hypertension: From pathophysiology mechanisms to treatment perspective Pharmacol Res 180 2022 106238
15 Abid S. Marcos E. Parpaleix A. Amsellem V. Breau M. Houssaini A. CCR2/CCR5-mediated macrophage-smooth muscle cell crosstalk in pulmonary hypertension Eur Respir J 54 2019
16 Amsellem V. Lipskaia L. Abid S. Poupel L. Houssaini A. Quarck R. CCR5 as a treatment target in pulmonary arterial hypertension Circulation 130 2014 880 891 24993099
17 Gauthier M. Kale S.L. Oriss T.B. Scholl K. Das S. Yuan H. Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation J Allergy Clin Immunol 149 2022 113 124 e7 34146578
18 Costa C. Traves S.L. Tudhope S.J. Fenwick P.S. Belchamber K.B. Russell R.E. Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD Eur Respir J 47 2016 1093 1102 26965295
19 Ozga A.J. Chow M.T. Luster A.D. Chemokines and the immune response to cancer Immunity 54 2021 859 874 33838745
20 Cao S. Liu M. Sehrawat T.S. Shah V.H. Regulation and functional roles of chemokines in liver diseases Nat Rev Gastroenterol Hepatol 18 2021 630 647 33976393
21 Mamazhakypov A. Viswanathan G. Lawrie A. Schermuly R.T. Rajagopal S. The role of chemokines and chemokine receptors in pulmonary arterial hypertension Br J Pharmacol 178 2021 72 89 31399998
22 White G.E. Iqbal A.J. Greaves D.R. CC chemokine receptors and chronic inflammation–therapeutic opportunities and pharmacological challenges Pharmacol Rev 65 2013 47 89 23300131
23 Sánchez-Gloria J.L. Carbó R. Buelna-Chontal M. Osorio-Alonso H. Henández-Díazcouder A. de la Fuente-León R.L. Cold exposure aggravates pulmonary arterial hypertension through increased miR-146a-5p, miR-155-5p and cytokines TNF-α, IL-1β, and IL-6 Life Sci 287 2021 120091
24 Huang Y. Lin F. Tang R. Bao C. Zhou Q. Ye K. Gut Microbial Metabolite Trimethylamine N-Oxide Aggravates Pulmonary Hypertension Am J Respir Cell Mol Biol 66 2022 452 460 35100519
25 Ross D.J. Strieter R.M. Fishbein M.C. Ardehali A. Belperio J.A. Type I immune response cytokine-chemokine cascade is associated with pulmonary arterial hypertension J Heart Lung Transplant 31 2012 865 873 22658713
26 Yang J.M. Zhou R. Zhang M. Tan H.R. Yu J.Q. Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response Molecules 23 2018
27 Upton P.D. Park J.E.S. De Souza P.M. Davies R.J. Griffiths M.J.D. Wort S.J. Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells J Cell Sci 133 2020
28 Wei Y. Yang L. Pandeya A. Cui J. Zhang Y. Li Z. Pyroptosis-Induced Inflammation and Tissue Damage J Mol Biol 434 2022 167301
29 Yu P. Zhang X. Liu N. Tang L. Peng C. Chen X. Pyroptosis: mechanisms and diseases Signal Transduct Target Ther 6 2021 128 33776057
30 Zeng C. Wang R. Tan H. Role of Pyroptosis in Cardiovascular Diseases and its Therapeutic Implications Int J Biol Sci 15 2019 1345 1357 31337966
31 Huang Y. Xu W. Zhou R. NLRP3 inflammasome activation and cell death Cell Mol Immunol 18 2021 2114 2127 34321623
32 Rao Z. Zhu Y. Yang P. Chen Z. Xia Y. Qiao C. Pyroptosis in inflammatory diseases and cancer Theranostics 12 2022 4310 4329 35673561
33 Sun Y. Liu S. Chen C. Yang S. Pei G. Lin M. The mechanism of programmed death and endoplasmic reticulum stress in pulmonary hypertension Cell Death Discov 9 2023 78 36841823
34 Liu S.F. Nambiar Veetil N. Li Q. Kucherenko M.M. Knosalla C. Kuebler W.M. Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening Front Immunol 13 2022 959209
35 Hosokawa S. Haraguchi G. Sasaki A. Arai H. Muto S. Itai A. Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354 Cardiovasc Res 99 2013 35 43 23631839
36 Zhang M. Xin W. Yu Y. Yang X. Ma C. Zhang H. Programmed death-ligand 1 triggers PASMCs pyroptosis and pulmonary vascular fibrosis in pulmonary hypertension J Mol Cell Cardiol 138 2020 23 33 31733200
37 Xing Y. Zhao J. Zhou M. Jing S. Zhao X. Mao P. The LPS induced pyroptosis exacerbates BMPR2 signaling deficiency to potentiate SLE-PAH Faseb j 35 2021 e22044 34818449
38 Cuthbertson I. Morrell N.W. Caruso P. BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension Circ Res 132 2023 109 126 36603064
39 Liu T. Zou X.Z. Huang N. Ge X.Y. Yao M.Z. Liu H. miR-27a promotes endothelial-mesenchymal transition in hypoxia-induced pulmonary arterial hypertension by suppressing BMP signaling Life Sci 227 2019 64 73 31004656
40 Morrell N.W. Aldred M.A. Chung W.K. Elliott C.G. Nichols W.C. Soubrier F. Genetics and genomics of pulmonary arterial hypertension Eur Respir J 53 2019
41 Kiskin F.N. Chang C.H. Huang C.J.Z. Kwieder B. Cheung C. Dunmore B.J. Contributions of BMPR2 Mutations and Extrinsic Factors to Cellular Phenotypes of Pulmonary Arterial Hypertension Revealed by Induced Pluripotent Stem Cell Modeling Am J Respir Crit Care Med 198 2018 271 325 29547009
42 Hurst L.A. Dunmore B.J. Long L. Crosby A. Al-Lamki R. Deighton J. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling Nat Commun 8 2017 14079 28084316
43 Pullamsetti S.S. Mamazhakypov A. Weissmann N. Seeger W. Savai R. Hypoxia-inducible factor signaling in pulmonary hypertension J Clin Invest 130 2020 5638 5651 32881714
44 Yu Y.R. Mao L. Piantadosi C.A. Gunn M.D. CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension Am J Respir Cell Mol Biol 48 2013 647 654 23492191
45 Amsellem V. Abid S. Poupel L. Parpaleix A. Rodero M. Gary-Bobo G. Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension Am J Respir Cell Mol Biol 56 2017 597 608 28125278
46 Yu Y.A. Malakhau Y. Yu C.A. Phelan S.J. Cumming R.I. Kan M.J. Nonclassical Monocytes Sense Hypoxia, Regulate Pulmonary Vascular Remodeling, and Promote Pulmonary Hypertension J Immunol 204 2020 1474 1485 31996456
47 Zhang W. Zhu T. Wu W. Ge X. Xiong X. Zhang Z. LOX-1 mediated phenotypic switching of pulmonary arterial smooth muscle cells contributes to hypoxic pulmonary hypertension Eur J Pharmacol 818 2018 84 95 29069578
48 Delaney C. Davizon-Castillo P. Allawzi A. Posey J. Gandjeva A. Neeves K. Platelet activation contributes to hypoxia-induced inflammation Am J Physiol Lung Cell Mol Physiol 320 2021 L413 L421 33264579
49 Herrero-Cervera A. Soehnlein O. Kenne E. Neutrophils in chronic inflammatory diseases Cell Mol Immunol 19 2022 177 191 35039631
50 Filippi M.D. Neutrophil transendothelial migration: updates and new perspectives Blood 133 2019 2149 2158 30898863
51 Quarck R. Wynants M. Verbeken E. Meyns B. Delcroix M. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension Eur Respir J 46 2015 431 443 26113681
52 Fu J. Chen Y.F. Zhao X. Creighton J.R. Guo Y. Hage F.G. Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling Arterioscler Thromb Vasc Biol 34 2014 1539 1547 24790141
53 Fang P. Li X. Dai J. Cole L. Camacho J.A. Zhang Y. Immune cell subset differentiation and tissue inflammation J Hematol Oncol 11 2018 97 30064449
54 Florentin J. Coppin E. Vasamsetti S.B. Zhao J. Tai Y.Y. Tang Y. Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes J Immunol 200 2018 3612 3625 29632145
55 Guilliams M. Mildner A. Yona S. Developmental and Functional Heterogeneity of Monocytes Immunity 49 2018 595 613 30332628
56 Frodermann V. Nahrendorf M. Macrophages and Cardiovascular Health Physiol Rev 98 2018 2523 2569 30156496
57 Mercier O. Arthur Ataam J. Langer N.B. Dorfmüller P. Lamrani L. Lecerf F. Abnormal pulmonary endothelial cells may underlie the enigmatic pathogenesis of chronic thromboembolic pulmonary hypertension J Heart Lung Transplant 36 2017 305 314 27793518
58 Al-Qazazi R. Lima P.D.A. Prisco S.Z. Potus F. Dasgupta A. Chen K.H. Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension Am J Respir Crit Care Med 206 2022 608 624 35699679
59 Griffith J.W. Sokol C.L. Luster A.D. Chemokines and chemokine receptors: positioning cells for host defense and immunity Annu Rev Immunol 32 2014 659 702 24655300
60 Vivier E. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Innate Lymphoid Cells: 10 Years On Cell 174 2018 1054 1066 30142344
61 Meng X. Yang J. Dong M. Zhang K. Tu E. Gao Q. Regulatory T cells in cardiovascular diseases Nat Rev Cardiol 13 2016 167 179 26525543
62 van Uden D. Koudstaal T. van Hulst J.A.C. van den Bosch T.P.P. Vink M. Bergen I.M. Evidence for a Role of CCR6+ T Cells in Chronic Thromboembolic Pulmonary Hypertension Front Immunol 13 2022 861450
63 Perros F. Dorfmüller P. Montani D. Hammad H. Waelput W. Girerd B. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension Am J Respir Crit Care Med 185 2012 311 321 22108206
64 Qiu H. He Y. Ouyang F. Jiang P. Guo S. Guo Y. The Role of Regulatory T Cells in Pulmonary Arterial Hypertension J Am Heart Assoc 8 2019 e014201 31771439
65 Zeng H. Liu X. Zhang Y. Identification of Potential Biomarkers and Immune Infiltration Characteristics in Idiopathic Pulmonary Arterial Hypertension Using Bioinformatics Analysis Front Cardiovasc Med 8 2021 624714
66 Chu Y. Xiangli X. Xiao W. Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice Mol Med Rep 11 2015 3181 3187 25523119
67 Qi D. Wei M. Jiao S. Song Y. Wang X. Xie G. Hypoxia inducible factor 1α in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment Cell Death Dis 10 2019 544 31320613
68 Zamanian R.T. Badesch D. Chung L. Domsic R.T. Medsger T. Pinckney A. Safety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Multicenter, Double-Blind, Randomized, Placebo-controlled Trial Am J Respir Crit Care Med 204 2021 209 221 33651671
69 Zitti B. Bryceson Y.T. Natural killer cells in inflammation and autoimmunity Cytokine Growth Factor Rev 42 2018 37 46 30122459
70 Franklin M. Connolly E. Hussell T. Recruited and Tissue-Resident Natural Killer Cells in the Lung During Infection and Cancer Front Immunol 13 2022 887503
71 Kim J.H. Chung D.H. CD1d-restricted IFN-γ-secreting NKT cells promote immune complex-induced acute lung injury by regulating macrophage-inflammatory protein-1α production and activation of macrophages and dendritic cells J Immunol 186 2011 1432 1441 21191075
72 Liu J. Zhang X. Cheng Y. Cao X. Dendritic cell migration in inflammation and immunity Cell Mol Immunol 18 2021 2461 2471 34302064
73 Worbs T. Hammerschmidt S.I. Förster R. Dendritic cell migration in health and disease Nat Rev Immunol 17 2017 30 48 27890914
74 Tiberio L. Del Prete A. Schioppa T. Sozio F. Bosisio D. Sozzani S. Chemokine and chemotactic signals in dendritic cell migration Cell Mol Immunol 15 2018 346 352 29563613
75 van Uden D. Koudstaal T. van Hulst J.A.C. Bergen I.M. Gootjes C. Morrell N.W. Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice Int J Mol Sci 22 2021
76 Guignabert C. Dendritic Cells in Pulmonary Hypertension: Foot Soldiers or Hidden Enemies? Am J Respir Cell Mol Biol 63 2020 551 552 32804536
77 Hautefort A. Girerd B. Montani D. Cohen-Kaminsky S. Price L. Lambrecht B.N. T-helper 17 cell polarization in pulmonary arterial hypertension Chest 147 2015 1610 1620 25429518
78 Olivera A. Beaven M.A. Metcalfe D.D. Mast cells signal their importance in health and disease J Allergy Clin Immunol 142 2018 381 393 29454835
79 Moriyama H. Endo J. Pathophysiological Involvement of Mast Cells and the Lipid Mediators in Pulmonary Vascular Remodeling Int J Mol Sci 24 2023
80 Farha S. Sharp J. Asosingh K. Park M. Comhair S.A. Tang W.H. Mast cell number, phenotype, and function in human pulmonary arterial hypertension Pulm Circ 2 2012 220 228 22837863
81 Kubo F. Ariestanti D.M. Oki S. Fukuzawa T. Demizu R. Sato T. Loss of the adhesion G-protein coupled receptor ADGRF5 in mice induces airway inflammation and the expression of CCL2 in lung endothelial cells Respir Res 20 2019 11 30654796
82 Salomonsson M. Dahlin J.S. Ungerstedt J. Hallgren J. Localization-Specific Expression of CCR1 and CCR5 by Mast Cell Progenitors Front Immunol 11 2020 321 32174921
83 Iype J. Fux M. Basophils Orchestrating Eosinophils' Chemotaxis and Function in Allergic Inflammation Cells 2021 10 35011571
84 Stone K.D. Prussin C. Metcalfe D.D. IgE, mast cells, basophils, and eosinophils J Allergy Clin Immunol 125 2010 S73 S80 20176269
85 Shu T. Zhang J. Zhou Y. Chen Z. Li J. Tang Q. Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA Eur Respir J 61 2023
86 Motomura Y. Morita H. Moro K. Nakae S. Artis D. Endo T.A. Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation Immunity 40 2014 758 771 24837103
87 Yu H. Lin L. Zhang Z. Zhang H. Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study Signal Transduct Target Ther 5 2020 209 32958760
88 Barnabei L. Laplantine E. Mbongo W. Rieux-Laucat F. Weil R. NF-κB: At the Borders of Autoimmunity and Inflammation Front Immunol 12 2021 716469
89 Mei L. Zheng Y.M. Song T. Yadav V.R. Joseph L.C. Truong L. Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway Nat Commun 11 2020 3527 32669538
90 Li Y. Yang L. Dong L. Yang Z.W. Zhang J. Zhang S.L. Crosstalk between the Akt/mTORC1 and NF-κB signaling pathways promotes hypoxia-induced pulmonary hypertension by increasing DPP4 expression in PASMCs Acta Pharmacol Sin 40 2019 1322 1333 31316183
91 Chen T. Su S. Yang Z. Zhang D. Li Z. Lu D. Srolo Bzhtang reduces inflammation and vascular remodeling via suppression of the MAPK/NF-κB signaling pathway in rats with pulmonary arterial hypertension J Ethnopharmacol 297 2022 115572
92 Zhai C. Shi W. Feng W. Zhu Y. Wang J. Li S. Activation of AMPK prevents monocrotaline-induced pulmonary arterial hypertension by suppression of NF-κB-mediated autophagy activation Life Sci 208 2018 87 95 30009823
93 Hu X. Li J. Fu M. Zhao X. Wang W. The JAK/STAT signaling pathway: from bench to clinic Signal Transduct Target Ther 6 2021 402 34824210
94 Roger I. Milara J. Montero P. Cortijo J. The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension Int J Mol Sci 22 2021
95 Yerabolu D. Weiss A. Kojonazarov B. Boehm M. Schlueter B.C. Ruppert C. Targeting Jak-Stat Signaling in Experimental Pulmonary Hypertension Am J Respir Cell Mol Biol 64 2021 100 114 33052714
96 Wei W.C. Liaw C.C. Tsai K.C. Chiou C.T. Tseng Y.H. Chiou W.F. Targeting spike protein-induced TLR/NET axis by COVID-19 therapeutic NRICM102 ameliorates pulmonary embolism and fibrosis Pharmacol Res 184 2022 106424
97 Mathien S. Tesnière C. Meloche S. Regulation of Mitogen-Activated Protein Kinase Signaling Pathways by the Ubiquitin-Proteasome System and Its Pharmacological Potential Pharmacol Rev 73 2021 263 296 34732541
98 Ullah R. Yin Q. Snell A.H. Wan L. RAF-MEK-ERK pathway in cancer evolution and treatment Semin Cancer Biol 85 2022 123 154 33992782
99 Kciuk M. Gielecińska A. Budzinska A. Mojzych M. Kontek R. Metastasis and MAPK Pathways Int J Mol Sci 23 2022
100 Burgos R.A. Alarcón P. Quiroga J. Manosalva C. Hancke J. Andrographolide, an Anti-Inflammatory Multitarget Drug: All Roads Lead to Cellular Metabolism Molecules 26 2020
101 Shafiq M. Jagavelu K. Iqbal H. Yadav P. Chanda D. Verma N.K. Inhibition of Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2) is Protective in Pulmonary Hypertension Hypertension 77 2021 1248 1259 33641361
102 Su L. Li X. Mao X. Xu T. Zhang Y. Li S. Circ-Ntrk2 acts as a miR-296-5p sponge to activate the TGF-β1/p38 MAPK pathway and promote pulmonary hypertension and vascular remodelling Respir Res 24 2023 78 36915149
103 Chun C. Yang W. Xueding C. Qi Z. Xiaoying H. Honglei X. Resveratrol downregulates acute pulmonary thromboembolism-induced pulmonary artery hypertension via p38 mitogen-activated protein kinase and monocyte chemoattractant protein-1 signaling in rats Life Sci 90 2012 721 727 22507635
104 Guo M. Zhang M. Cao X. Fang X. Li K. Qin L. Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension Respir Res 23 2022 6 35016680
105 Zhou B. Lin W. Long Y. Yang Y. Zhang H. Wu K. Notch signaling pathway: architecture, disease, and therapeutics Signal Transduct Target Ther 7 2022 95 35332121
106 Morris H.E. Neves K.B. Montezano A.C. MacLean M.R. Touyz R.M. Notch3 signalling and vascular remodelling in pulmonary arterial hypertension Clin Sci (Lond) 133 2019 2481 2498 31868216
107 Zhang Y, Hernandez M, Gower J, Winicki N, Morataya X, Alvarez S, et al. JAGGED-NOTCH3 signaling in vascular remodeling in pulmonary arterial hypertension. Sci Transl Med 2022;14:eabl5471.
108 Liu H. Wang S. Chen Q. Ge X. Ning H. Guo Y. Natural Targeting Potent ROS-Eliminating Tungsten-Based Polyoxometalate Nanodots for Efficient Treatment of Pulmonary Hypertension Adv Healthc Mater 12 2023 e2300252 37196347
109 Condon D.F. Agarwal S. Chakraborty A. Auer N. Vazquez R. Patel H. Novel Mechanisms Targeted by Drug Trials in Pulmonary Arterial Hypertension Chest 161 2022 1060 1072 34655569
110 Parpaleix A. Amsellem V. Houssaini A. Abid S. Breau M. Marcos E. Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension Eur Respir J 48 2016 470 483 27418552
111 Masaki T. Okazawa M. Asano R. Inagaki T. Ishibashi T. Yamagishi A. Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension Proc Natl Acad Sci U S A 118 2021
112 Xiao Q. Li X. Li Y. Wu Z. Xu C. Chen Z. Biological drug and drug delivery-mediated immunotherapy Acta Pharm Sin B 11 2021 941 960 33996408
113 Li B. He W. Ye L. Zhu Y. Tian Y. Chen L. Targeted delivery of sildenafil for inhibiting pulmonary vascular remodeling Hypertension 73 2019 703 711 30636546
114 Lazo R.E.L. Mengarda M. Almeida S.L. Caldonazo A. Espinoza J.T. Murakami F.S. Advanced formulations and nanotechnology-based approaches for pulmonary delivery of sildenafil: A scoping review J Control Release 350 2022 308 323 35995298
115 Wang A. Cao S. Stowe J.C. Valdez-Jasso D. Substrate Stiffness and Stretch Regulate Profibrotic Mechanosignaling in Pulmonary Arterial Adventitial Fibroblasts Cells 10 2021
