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Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

38820208
202404-0844ED
10.1164/rccm.202404-0844ED
Editorials
Unveiling the Neuron-mediated Group 2 Innate Lymphoid Cell Activation in Human Asthma
https://orcid.org/0000-0001-8853-6149
Kabata Hiroki 1
https://orcid.org/0000-0002-3537-7735
Ueki Shigeharu 2
1 Department of Pulmonary Medicine
Keio University School of Medicine
Tokyo, Japan
2 Department of General Internal Medicine and Clinical Laboratory Medicine
Akita University Graduate School of Medicine
Akita, Japan
31 5 2024
15 9 2024
31 5 2024
210 6 701703
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).

Japan Society for the Promotion of Science 10.13039/501100001691 24K11593
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pmcNeuroimmune interactions play a pivotal role in the pathophysiology of allergic diseases. Neuropeptides generated by neurons directly affect immune cells, whereas inflammatory mediators produced by immune cells stimulate neurons. Recent evidence indicates that peripheral neurons and immune cells coexist in close proximity in tissues, mutually influencing each other locally (1).

In asthma, lymphocytes involved in the pathogenesis of type 2 inflammation include T-helper type 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s). Th2 cells, induced by acquired immunity, participate in antigen-specific type 2 inflammation. On the other hand, ILC2s lack receptors for antigen recognition and are directly activated by cytokines and neuropeptides to induce type 2 inflammation. Patients with asthma experience “asthma attacks,” characterized by a bimodal drop in FEV1 in response to various stimuli, especially those sensitized to specific allergens when they inhale the allergens. Previously, Chen, Sehmi, and colleagues and Machida, Sehmi, and colleagues reported that ILC2s are induced in sputum in patients with mild asthma within 24 hours of inhaling allergens, followed by a delayed induction of Th2 cells (2, 3). Despite allergen inhalation typically triggering antigen-specific Th2 cells, it is noteworthy that ILC2s, which do not recognize antigens, are also induced earlier. Similar findings have been reported in nasal (4) and BAL fluid (5) samples, indicating that allergen inhalation induces the release of epithelial cell–derived cytokines (IL-33, thymic stromal lymphopoietin), chemokines (CCL17, CCL22, CXCL12), and lipid mediators (prostaglandin D2), facilitating the induction of ILC2s during the acute phase of asthma attacks. However, it has not been reported whether neuropeptides are involved in the induction of ILC2s in patients with asthma.

In this issue of the Journal, Ju, Sehmi, and colleagues (pp. 755–765) demonstrate the involvement of neuromedin U (NMU) in the early activation of ILC2s upon allergen inhalation in patients with asthma (Figure 1) (6). NMU, a member of the neuromedin superfamily, is released from cholinergic and sensory nerves and serves various functions, including smooth muscle contraction, blood pressure regulation, metabolic homeostasis, circadian rhythm regulation, and tumorigenesis (7). In 2017, three different research groups highlighted the role of NMU in murine ILC2s; the NMU receptor Nmur1 is specifically expressed on ILC2s among immune cells, and NMU directly activates ILC2s to produce IL-5, IL-9, IL-13, and amphiregulin (8–10). Currently, ILC2-specific conditional knockout mice have been generated using Nmur1 (11–13). However, in humans, NMUR1 is not expressed specifically on ILC2s, being expressed on a variety of immune cells except neutrophils (14).

Figure 1. Neuromedin U (NMU)-NMUR1 axis in allergen-induced early activation of group 2 innate lymphoid cells.

Ju, Sehmi, and colleagues confirmed dual bronchoconstriction and increased airway hyperresponsiveness after allergen inhalation in patients with mild allergic asthma. Seven hours after allergen inhalation, they found an increase in ILC2s in sputum, especially NMUR1+ ILC2s; NMUR1+ ILC2s showed higher rates of IL-5 and IL-13 production, which correlated with the percentage of eosinophils in sputum. Next, in experiments using peripheral blood ILC2s, they found that IL-33 and thymic stromal lymphopoietin stimulation upregulated NMUR1 expression in ILC2s. Furthermore, NMU stimulation induced IL-5 and IL-13 production from ILC2s faster than IL-33 stimulation, via mitogen-activated protein kinase kinase, calcineurin/nuclear factor of activated T cells, and phosphatidylinositol-3-kinase pathways. Finally, they show that IL-33–induced NMUR1 expression in ILC2s is suppressed by corticosteroids, and NMUR1 expression in sputum was shown to be lower in patients with moderate-severe asthma using high-dose inhaled corticosteroids.

Neuropeptides have been reported to have a profound effect on ILC2s (15), but most studies have been conducted in mice. This study is particularly valuable because it is the first to demonstrate that NMUR1+ ILC2s are increased in patients with asthma after allergen inhalation. However, no rise in sputum NMU concentrations after inhalation was observed. Although NMU acts faster than IL-33 on ILC2s, it is not yet certain whether the early induction and activation of ILC2s is solely dependent on the NMU-NMUR1 pathway. In addition, NMUR1 expression was inhibited by corticosteroids in vitro, and its expression was lower in patients with moderate-severe asthma using high-dose inhaled corticosteroids, suggesting that the NMU-NMUR1 pathway may not be a promising target for severe asthma or steroid-resistant conditions. In humans, NMUR1 expression is known not only in ILC2s but also in Th2 cells, raising questions about its expression evaluation in T cells after allergen inhalation. Advanced evaluation of immune cells in sputum after allergen inhalation using more comprehensive methods (e.g., single-cell RNA sequencing and/or mass cytometry) could offer deeper insights.

Nevertheless, human studies are crucial because of the inherent differences between humans and animals. Investigating the role of neuropeptides in individuals with heterogeneous asthma poses greater challenges than well-controlled animal studies. This paper represents a pioneering effort to explore the involvement of neuropeptides in humans, offering valuable insights. The future prospects for enhancing our understanding of neuroimmune interactions in human allergies are promising and exciting.

Acknowledgment

The authors are grateful to Satomi Misawa for creating the illustration.

Supported by the Japan Society for the Promotion of Science (24K11593).

Originally Published in Press as DOI: 10.1164/rccm.202404-0844ED on May 31, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
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