
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.123
vdae090.123
Final Category: Supportive Care, Palliative Care and QOL
AcademicSubjects/MED00300
AcademicSubjects/MED00310
QSPC-06 TIME-SERIES SINGLE-CELL ANALYSES REVEAL INCESSANT REWIRING OF MICROGLIA AFTER OF CRANIAL IRRADIATION
Osman Ahmed Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Romero Alejandro Lastra Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Preka Efthalia Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Pizzirusso Giusy Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

Arroyo-Garcia Luis Enrique Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

Zisiadis Georgios Alkis Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Oliva-Vilarnau Nuria Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Seitz Thea Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Zhou Kai Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Isla Arturo Gonzalez Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

Sun Ying Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

Zhu Changlian Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

Rodrigues Carlos Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Fisahn André Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

Fragkopoulou Adamantia Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Lauschke Volker Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

Betsholtz Christer Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
Integrated Cardio-Metabolic Centre, Department of Medicine, Karolinska Institute, Stockholm, Sweden

Blomgren Klas Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i37i38
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Cranial irradiation (IR) is one of the pillars of treatment of brain tumors and metastases, but it causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is believed to contribute to this, but its dynamics and consequences on brain function remain poorly understood. Here, we performed longitudinal molecular and cellular profiling of the irradiated mouse hippocampus, a key brain structure for cognitive tasks, using single cell transcriptomics and computational analyses, proteomics and histology, covering multiple time points, from 6 hours to 1 year after IR. We found that IR induced biphasic inflammatory waves, and microglia were the key orchestrating cells. The first wave occurred within the first 24 hours after IR, triggered by the death of neural progenitors in the dentate gyrus. The second, delayed wave occurred 2 weeks after IR, coupling interferon signaling to mitotic progression, and a subsequent induction of temporally regulated subtypes. Trajectory analysis uncovered that this subset of microglia drives microglial mitotic progression, cell death, or a senescent-like phenotype predominantly observed 6 weeks after IR. At this timepoint, the levels of cytokines known to have negative effects on cognition, like tumor necrosis factor and interleukin-6, were increased, coinciding with neuronal asynchrony of the hippocampal circuitry. We also found that IR caused progressive microglial loss and that they fail to repopulate the empty territories by self-renewal, leading to infiltration of peripheral macrophages to repopulate the hippocampus and differentiate into microglia-like cells by 6 months after IR. After 1 year, microglial alterations were largely related to neuronal and synaptic plasticity, and again coinciding with neuronal asynchrony. Thus, the inflammation profile in the hippocampus after IR is dynamic, and therapies targeting inflammation should be tailored accordingly.
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