Gas6 Promotes Microglia Efferocytosis and Suppresses Inflammation Through Activating Axl/Rac1 Signaling in Subarachnoid Hemorrhage Mice

作者全名："Tang, Junjia; Jin, Yichao; Jia, Feng; Lv, Tao; Manaenko, Anatol; Zhang, Lin-Feng; Zhang, Zeyu; Qi, Xin; Xue, Yajun; Zhao, Bin; Zhang, Xiaohua; Zhang, John H.; Lu, Jianfei; Hu, Qin"

作者地址："[Tang, Junjia; Jin, Yichao; Jia, Feng; Lv, Tao; Zhang, Lin-Feng; Zhang, Zeyu; Zhao, Bin; Zhang, Xiaohua; Hu, Qin] Shanghai Jiao Tong Univ, Ren Ji Hosp, Dept Neurosurg, Sch Med, Shanghai 200127, Peoples R China; [Tang, Junjia; Xue, Yajun] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Neurosurg, Sch Med, Shanghai 201620, Peoples R China; [Manaenko, Anatol] Chongqing Med Univ, Dept Neurol, Affiliated Hosp 1, Chongqing, Peoples R China; [Qi, Xin; Lu, Jianfei] Shanghai Jiao Tong Univ, Dept Physiol & Anat, Discipline Neurosci, Sch Med, Shanghai 200025, Peoples R China; [Zhang, John H.] Loma Linda Univ, Dept Physiol & Pharmacol, Loma Linda, CA 92350 USA; [Lu, Jianfei] Shanghai Jiao Tong Univ, Songjiang Inst, Sch Med, Shanghai 201600, Peoples R China; [Lu, Jianfei] Shanghai Jiao Tong Univ, Songjiang Hosp, Sch Med, Shanghai 201600, Peoples R China"

通信作者："Hu, Q (通讯作者)，Shanghai Jiao Tong Univ, Ren Ji Hosp, Dept Neurosurg, Sch Med, Shanghai 200127, Peoples R China.; Lu, JF (通讯作者)，Shanghai Jiao Tong Univ, Dept Physiol & Anat, Discipline Neurosci, Sch Med, Shanghai 200025, Peoples R China.; Lu, JF (通讯作者)，Shanghai Jiao Tong Univ, Songjiang Inst, Sch Med, Shanghai 201600, Peoples R China.; Lu, JF (通讯作者)，Shanghai Jiao Tong Univ, Songjiang Hosp, Sch Med, Shanghai 201600, Peoples R China."

来源：TRANSLATIONAL STROKE RESEARCH

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000878019300001

JCR分区：Q1

影响因子：6.9

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Microglia efferocytosis; Gas6; Axl; Inflammation; Early brain injury; Subarachnoid hemorrhage

摘要："Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is characterized by rapid development of neuron apoptosis and dysregulated inflammatory response. Microglia efferocytosis plays a critical role in the clearance of apoptotic cells, attenuation of inflammation, and minimizing brain injury in various pathological conditions. Here, using a mouse SAH model, we aim to investigate whether microglia efferocytosis is involved in post-SAH inflammation and to determine the underlying signaling pathway. We hypothesized that TAM receptors and their ligands regulate this process. To prove our hypothesis, the expression and cellular location of TAM (Tyro3, Axl, and Mertk) receptors and their ligands growth arrest-specific 6 (Gas6) and Protein S (ProS1) were examined by PCR, western blots, and fluorescence immunostaining. Thirty minutes after SAH, mice received an intraventricular injection of recombinant Gas6 (rGas6) or recombinant ProS1 (rPros1) and underwent evaluations of inflammatory mediator expression, neurological deficits, and blood-brain barrier integrity at 24 h. Microglia efferocytosis of apoptotic neurons was analyzed in vivo and in vitro. The potential mechanism was determined by inhibiting or knocking down TAM receptors and Rac1 by specific inhibitors or siRNA. SAH induced upregulation of Axl and its ligand Gas6. The administration of rGas6 but not rPros1 promoted microglia efferocytosis, alleviated inflammation, and ameliorated SAH-induced BBB breakdown and neurological deficits. The beneficial effects of rGas6 were arrogated by inhibiting or knocking down Axl and Rac1. We concluded that rGas6 attenuated the development of early brain injury in mice after SAH by facilitating microglia efferocytosis and preventing inflammatory response, which is partly dependent on activation of Axl and Rac1."

基金机构："National Natural Science Foundation of China [82071283, 81601013, 31900686, 82271310]; Natural Science Foundation of Shanghai [22ZR1437700]; Science and Technology Commission of Shanghai Municipal [21ZR1439000]"

基金资助正文："This research was supported by grants from the National Natural Science Foundation of China No. 82071283 to Qin Hu, No. 81601013 to Junjia Tang, No. 31900686 to Jianfei Lu, and No. 82271310 to Feng Jia, the Natural Science Foundation of Shanghai 22ZR1437700 to Qin Hu, and Science and Technology Commission of Shanghai Municipal 21ZR1439000 to Feng Jia."