M2 macrophages mediate fibrotic scar formation in the early stages after cerebral ischemia in rats

作者全名："Huang, Jia-Gui; Ren, Jiang-Xia; Chen, Yue; Tian, Ming-Fen; Zhou, Li; Wen, Jun; Song, Xiao-Song; Wu, You-Lin; Yang, Qing-Huan; Jiang, Pei-Ran; Wang, Jia-Ni; Yang, Qin"

作者地址："[Huang, Jia-Gui; Ren, Jiang-Xia; Chen, Yue; Tian, Ming-Fen; Zhou, Li; Wen, Jun; Song, Xiao-Song; Wu, You-Lin; Yang, Qing-Huan; Jiang, Pei-Ran; Wang, Jia-Ni; Yang, Qin] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing, Peoples R China"

通信作者："Yang, Q (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing, Peoples R China."

来源：NEURAL REGENERATION RESEARCH

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001058059000026

JCR分区：Q2

影响因子：6.1

年份：2023

卷号：18

期号：10

开始页：2208

结束页：2218

文献类型：Article

关键词：central nervous system; extracellular matrix; fibronectin; fibrotic scar; macrophage; interleukin 4; ischemic cerebral injury; neurological function; Sonic hedgehog; transforming growth factor beta 1

摘要："In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury (within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4 (IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke."

基金机构："National Natural Science Foundation of China [82171456, 81971229]; Natural Science Foundation of Chongqing [cstc2021jcyj-msxmX0263]; Postgraduate Research and Innovation Project of Chongqing [CYB20151, CYS19182]"

基金资助正文："This study was supported by the National Natural Science Foundation of China, Nos. 82171456 (to QY), 81971229 (to QY); the Natural Science Foundation of Chongqing, No. cstc2021jcyj-msxmX0263 (to QY); and the Postgraduate Research and Innovation Project of Chongqing, Nos. CYB20151 (to QY), CYS19182 (to YC)."