JAK2/STAT3 Axis Intermediates Microglia/Macrophage Polarization During Cerebral Ischemia/Reperfusion Injury

Yi Zhong; Lijuan Gu; Yingze Ye; Hua Zhu; Bei Pu; Jinchen Wang; Yuntao Li; Sheng Qiu; Xiaoxing Xiong; Zhihong Jian

doi:10.1016/j.neuroscience.2022.05.016

JAK2/STAT3 Axis Intermediates Microglia/Macrophage Polarization During Cerebral Ischemia/Reperfusion Injury

Neuroscience. 2022 Aug 1:496:119-128. doi: 10.1016/j.neuroscience.2022.05.016. Epub 2022 May 20.

Authors

Yi Zhong¹, Lijuan Gu², Yingze Ye¹, Hua Zhu¹, Bei Pu¹, Jinchen Wang¹, Yuntao Li³, Sheng Qiu⁴, Xiaoxing Xiong⁵, Zhihong Jian⁶

Affiliations

¹ Department of Neurosurgery, Renmin Hospital of Wuhan University, China.
² Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
³ Department of Neurosurgery, Renmin Hospital of Wuhan University, China; Department of Neurosurgery, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine (Huzhou Central Hospital), Huzhou, China.
⁴ Department of Neurosurgery, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine (Huzhou Central Hospital), Huzhou, China.
⁵ Department of Neurosurgery, Renmin Hospital of Wuhan University, China; Department of Neurosurgery, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine (Huzhou Central Hospital), Huzhou, China. Electronic address: xiaoxingxiong@whu.edu.cn.
⁶ Department of Neurosurgery, Renmin Hospital of Wuhan University, China. Electronic address: zhihong@whu.edu.cn.

PMID: 35598702
DOI: 10.1016/j.neuroscience.2022.05.016

Abstract

Background: Subtypes of microglia/macrophage regulate the inflammation in the opposite direction during ischemic stroke. JAK2/STAT3 signaling pathway participates in the development of stroke-related inflammation via ischemic stimulation. However, the relationship between JAK2/STAT3 pathway and microglia/macrophage phenotype transformation is unclear.

Methods: This study established a transient middle cerebral artery occlusion (tMCAO) model in male STAT3^f/f and STAT3^f/f LysM^cre+ mice and evaluated the neurological deficit on the 3rd day using Longa score. The brains were stained by TTC to determine the infarction volume. Western blotting and QPCR were used to determine the expression of JAK2/STAT3 pathway and microglia/macrophage-related markers. Immunofluorescence staining was used to detect the levels of polarization-related indexes. QPCR also assessed the effect of STAT3 knockout on inflammatory factors in the infarction. Moreover, established the OGD/R model using BV2 cells to further verify the role of STAT3 on microglia/macrophage polarization.

Results: For the conditioned STAT3-KO mice, the infarction was significantly increased after MCAO, accompanied by the aggravation of neurological deficit. Higher expression of iNOS and CD16/32 than Arg-1, Ym-1, and CD206 in vivo and in vitro, and decreased p-STAT3/STAT3 ratio in STAT3^f/f LysM^cre+ mice, while the p-JAK2/JAK2 ratio increased. In addition, increased M1/M2 ratio and elevated expression of IL-1β, IL-6, TNF-α with STAT3 deletion, as well as increased CD68⁺/iNOS⁺ cell numbers.

Conclusion: Collectively, these results reveal that JAK2/STAT3 signaling pathway regulates the microglia/macrophage polarization (skewing toward the M2 polarization) during the CIRI, thus alleviating brain damage. Therefore, approaches targeting JAK2/STAT3 activation are promising therapies for ischemic stroke.

Keywords: JAK2/STAT3; ischemic stroke; microglia/macrophage; polarization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Ischemia* / metabolism
Infarction, Middle Cerebral Artery / metabolism
Inflammation / metabolism
Ischemic Stroke*
Macrophages / metabolism
Male
Mice
Microglia / metabolism
Reperfusion Injury* / metabolism