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

INTRODUCTION: The 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 investi...

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Autores principales: Yang, Xiaosheng, Liu, Yang, Zhong, Weijie, Li, Yi, Zhang, Wenchuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304015/
https://www.ncbi.nlm.nih.gov/pubmed/37388740
http://dx.doi.org/10.3389/fimmu.2023.1178638
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author Yang, Xiaosheng
Liu, Yang
Zhong, Weijie
Li, Yi
Zhang, Wenchuan
author_facet Yang, Xiaosheng
Liu, Yang
Zhong, Weijie
Li, Yi
Zhang, Wenchuan
author_sort Yang, Xiaosheng
collection PubMed
description INTRODUCTION: The 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. METHODS: Netrin-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. RESULTS: Across 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. CONCLUSION: Our study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.
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spelling pubmed-103040152023-06-29 Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype Yang, Xiaosheng Liu, Yang Zhong, Weijie Li, Yi Zhang, Wenchuan Front Immunol Immunology INTRODUCTION: The 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. METHODS: Netrin-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. RESULTS: Across 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. CONCLUSION: Our study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery. Frontiers Media S.A. 2023-06-14 /pmc/articles/PMC10304015/ /pubmed/37388740 http://dx.doi.org/10.3389/fimmu.2023.1178638 Text en Copyright © 2023 Yang, Liu, Zhong, Li and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Yang, Xiaosheng
Liu, Yang
Zhong, Weijie
Li, Yi
Zhang, Wenchuan
Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
title Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
title_full Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
title_fullStr Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
title_full_unstemmed Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
title_short Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
title_sort netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304015/
https://www.ncbi.nlm.nih.gov/pubmed/37388740
http://dx.doi.org/10.3389/fimmu.2023.1178638
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