Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype

Xiaosheng Yang; Yang Liu; Weijie Zhong; Yi Li; Wenchuan Zhang

doi:10.3389/fimmu.2023.1178638

Frontiers in Immunology (Jun 2023)

Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype

Xiaosheng Yang,
Yang Liu,
Weijie Zhong,
Yi Li,
Wenchuan Zhang

Affiliations

Xiaosheng Yang: Department of Neurosurgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Yang Liu: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Weijie Zhong: Department of Neurosurgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Yi Li: Department of Neurosurgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Wenchuan Zhang: Department of Neurosurgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

DOI: https://doi.org/10.3389/fimmu.2023.1178638
Journal volume & issue: Vol. 14

Abstract

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IntroductionThe current approaches that are used to treat ischemic stroke suffer from poor targeting, lack of effectiveness, and potential off-target effects, necessitating the development of new therapeutic strategies to enhance neuronal cell survival and regeneration. This study aimed to investigate the role of microglial Netrin-1 in ischemic stroke, a topic that has not been fully understood.MethodsNetrin-1 levels and its primary receptor expressions were investigated in cerebral microglia from acute ischemic stroke patients and age-matched control subjects. A public database (GEO148350), which supplied RNAseq results for rat cerebral microglia in a middle cerebral artery occlusion (MCAO) model, was analyzed to assess the expression of Netrin-1, its major receptors, and genes related to macrophage function. A microglia-specific gene targeting approach and a delivery system allowing for crossing the blood-brain barrier were applied in a mouse model for ischemic stroke to investigate the role of microglial Netrin-1. Netrin-1 receptor signaling in microglia was observed and the effects on microglial phenotype, apoptosis, and migration were analyzed.ResultsAcross human patients, rat and mouse models, activation of Netrin-1 receptor signaling was mainly conducted via its receptor UNC5a in microglia, which resulted in a shift in microglial phenotype towards an anti-inflammatory or M2-like state, leading to a reduction in apoptosis and migration of microglia. Netrin-1-induced phenotypic change in microglia exerted protective effects on neuronal cells in vivo during ischemic stroke.ConclusionOur study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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