Microglial IL‐1RA ameliorates brain injury after ischemic stroke by inhibiting astrocytic CXCL1‐mediated neutrophil recruitment and microvessel occlusion

Author:

Huang Xiaoyan1,Guo Mingyan1,Zhang Yangfan1,Xie Jiatian2,Huang Rong1,Zuo Zhiyi3,Saw Phei Er45,Cao Minghui16ORCID

Affiliation:

1. Department of Anesthesiology Sun Yat‐Sen Memorial Hospital, Sun Yat‐Sen University Guangzhou China

2. Department of Neurology Sun Yat‐Sen Memorial Hospital, Sun Yat‐Sen University Guangzhou China

3. Department of Anesthesiology University of Virginia Charlottesville Virginia USA

4. Medical Research Center Sun Yat‐Sen Memorial Hospital, Sun Yat‐Sen University Guangzhou China

5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat‐Sen Memorial Hospital, Sun Yat‐Sen University Guangzhou China

6. Department of Anesthesiology Shenshan Medical Center, Sun Yat‐Sen Memorial Hospital, Sun Yat‐sen University Shanwei China

Abstract

AbstractAcute ischemic stroke (AIS), one of the leading causes of mortality worldwide, is characterized by a rapid inflammatory cascade resulting in exacerbation of ischemic brain injury. Microglia are the first immune responders. However, the role of postischemic microglial activity in ischemic brain injury remains far from being fully understood. Here, using the transgenic mouse line CX3CR1creER:R26iDTR to genetically ablate microglia, we showed that microglial deletion exaggerated ischemic brain injury. Associated with this worse outcome, there were increased neutrophil recruitment, microvessel blockade and blood flow stagnation in the acute phase, accompanied by transcriptional upregulation of chemokine (C‐X‐C motif) ligand 1 (CXCL1). Our study showed that microglial interleukin‐1 receptor antagonist (IL‐1RA) suppressed astrocytic CXCL1 expression induced by oxygen and glucose deprivation and inhibited neutrophil migration. Furthermore, neutralizing antibody therapy against CXCL1 or the administration of recombinant IL‐1RA protein reduced brain infarct volume and improved motor coordination performance of mice after ischemic stroke. Our study suggests that microglia protect against acute ischemic brain injury by secreting IL‐1RA to inhibit astrocytic CXCL1 expression, which reduces neutrophil recruitment and neutrophil‐derived microvessel occlusion.

Funder

Guangzhou Science, Technology and Innovation Commission

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Neurology

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