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

作　　者：Jia-Gui Huang Jiang-Xia Ren Yue Chen Ming-Fen Tian Li Zhou Jun Wen Xiao-Song Song You-Lin Wu Qing-Huan Yang Pei-Ran Jiang Jia-Ni Wang Qin Yang 

机构地区：[1]Department of Neurology,The First Affiliated Hospital of Chongqing Medical University,Chongqing,China

出　　处：《Neural Regeneration Research》2023年第10期2208-2218,共11页中国神经再生研究（英文版）

基　　金：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);the Postgraduate Research and Innovation Project of Chongqing,Nos.CYB20151 (to QY),CYS19182 (to YC)。

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.

关 键 词：central nervous system extracellular matrix FIBRONECTIN fibrotic scar macrophage interleukin 4 ischemic cerebral injury neurological function Sonic hedgehog transforming growth factorβ1 

分 类 号：R743.35[医药卫生—神经病学与精神病学]