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

Authors Yu X, Feng Y, Liu R, Chen Q

Received 25 January 2021

Accepted for publication 24 March 2021

Published 7 April 2021 Volume 2021:14 Pages 1271—1281

DOI https://doi.org/10.2147/JIR.S303053

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Ning Quan


Xinyuan Yu, Yanping Feng, Renzhong Liu, Qianxue Chen

Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China

Correspondence: Qianxue Chen
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
Tel +86 13607141618
Email [email protected]

Background: 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

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