Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4

Xinyuan Yu, Yanping Feng, Renzhong Liu, Qianxue Chen Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaCorrespondence: Qianxue ChenDepartment of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People&am...

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Autores principales:	Yu X, Feng Y, Liu R, Chen Q
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	therapeutic hypothermia interferon regulatory factor 4 ischemic stroke inflammation macrophage polarization Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/d10aeba937e44d41b87a0f83d201aa23
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spelling	oai:doaj.org-article:d10aeba937e44d41b87a0f83d201aa232021-12-02T14:25:43ZHypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-41178-7031https://doaj.org/article/d10aeba937e44d41b87a0f83d201aa232021-04-01T00:00:00Zhttps://www.dovepress.com/hypothermia-protects-mice-against-ischemic-stroke-by-modulating-macrop-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Xinyuan Yu, Yanping Feng, Renzhong Liu, Qianxue Chen Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaCorrespondence: Qianxue ChenDepartment of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaTel +86 13607141618Email chen_qx2006@163.comBackground: Therapeutic hypothermia (TH) has been proven to be protective in ischemic stroke (IS) due to its anti-inflammatory capacity. Recently, the interferon regulatory factor 4 (IRF4) has been characterized as a central regulator of neuroinflammation in IS. Here we aim to determine whether IFR4 contributes to the neuroprotective effects of TH in IS.Methods: In the present study, IRF4 knockout (IRF4−/-) and wild-type (IRF4+/+) mice were treated with or without TH after IS. Cerebral IRF4 expression, the production of pro-inflammatory and anti-inflammatory cytokines and macrophage polarization were determined at 8 hours after reperfusion. In addition, cerebral infarct volume and neurological function were evaluated at 7 days after IS.Results: TH attenuates IS together with enhanced IRF4 expression as well as reduced production of pro-inflammatory cytokines. In addition, TH increased M2 macrophage polarization while inhibited M1 macrophage polarization. However, IRF4 knockout worsens neurological outcomes of stoke mice. The expression of pro-inflammatory cytokines were markedly increased in IRF4−/- mice as compared with IRF4+/+ mice at 8 h after stroke. Moreover, IRF4 knockout driven the macrophage polarization toward M1phenotype at 8 h after stroke. Most importantly, IRF4 knockout abolished the neuroprotective and anti-inflammatory effects of TH in IS.Conclusion: Together, we report for the first time that TH attenuates neuroinflammation following IS by modulating M1/M2 macrophage polarization through the upregulation of IRF4 expression.Keywords: therapeutic hypothermia, interferon regulatory factor 4, ischemic stroke, inflammation, macrophage polarizationYu XFeng YLiu RChen QDove Medical Pressarticletherapeutic hypothermiainterferon regulatory factor 4ischemic strokeinflammationmacrophage polarizationPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 1271-1281 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	therapeutic hypothermia interferon regulatory factor 4 ischemic stroke inflammation macrophage polarization Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	therapeutic hypothermia interferon regulatory factor 4 ischemic stroke inflammation macrophage polarization Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Yu X Feng Y Liu R Chen Q Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4
description	Xinyuan Yu, Yanping Feng, Renzhong Liu, Qianxue Chen Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaCorrespondence: Qianxue ChenDepartment of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaTel +86 13607141618Email chen_qx2006@163.comBackground: Therapeutic hypothermia (TH) has been proven to be protective in ischemic stroke (IS) due to its anti-inflammatory capacity. Recently, the interferon regulatory factor 4 (IRF4) has been characterized as a central regulator of neuroinflammation in IS. Here we aim to determine whether IFR4 contributes to the neuroprotective effects of TH in IS.Methods: In the present study, IRF4 knockout (IRF4−/-) and wild-type (IRF4+/+) mice were treated with or without TH after IS. Cerebral IRF4 expression, the production of pro-inflammatory and anti-inflammatory cytokines and macrophage polarization were determined at 8 hours after reperfusion. In addition, cerebral infarct volume and neurological function were evaluated at 7 days after IS.Results: TH attenuates IS together with enhanced IRF4 expression as well as reduced production of pro-inflammatory cytokines. In addition, TH increased M2 macrophage polarization while inhibited M1 macrophage polarization. However, IRF4 knockout worsens neurological outcomes of stoke mice. The expression of pro-inflammatory cytokines were markedly increased in IRF4−/- mice as compared with IRF4+/+ mice at 8 h after stroke. Moreover, IRF4 knockout driven the macrophage polarization toward M1phenotype at 8 h after stroke. Most importantly, IRF4 knockout abolished the neuroprotective and anti-inflammatory effects of TH in IS.Conclusion: Together, we report for the first time that TH attenuates neuroinflammation following IS by modulating M1/M2 macrophage polarization through the upregulation of IRF4 expression.Keywords: therapeutic hypothermia, interferon regulatory factor 4, ischemic stroke, inflammation, macrophage polarization
format	article
author	Yu X Feng Y Liu R Chen Q
author_facet	Yu X Feng Y Liu R Chen Q
author_sort	Yu X
title	Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4
title_short	Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4
title_full	Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4
title_fullStr	Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4
title_full_unstemmed	Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4
title_sort	hypothermia protects mice against ischemic stroke by modulating macrophage polarization through upregulation of interferon regulatory factor-4
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/d10aeba937e44d41b87a0f83d201aa23
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_version_	1718391397762990080

Hypothermia Protects Mice Against Ischemic Stroke by Modulating Macrophage Polarization Through Upregulation of Interferon Regulatory Factor-4

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