Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury.
Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury.
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Mer 调节小胶质细胞/巨噬细胞 M1/M2 极化并减轻创伤性脑损伤后的神经炎症
DOI：
10.1186/s12974-020-02041-7
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发表时间：
2021-01-05
影响因子：
9.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Wu H;Zheng J;Xu S;Fang Y;Wu Y;Zeng J;Shao A;Shi L;Lu J;Mei S;Wang X;Guo X;Wang Y;Zhao Z;Zhang J
背景：创伤性脑损伤（TBI）是世界范围内导致死亡和残疾的主要原因。小胶质细胞/巨噬细胞活化和神经炎症是创伤性脑损伤后的关键细胞事件，但其调控和功能机制尚不清楚。髓细胞上皮-生殖酪氨酸激酶（Mer）是酪氨酸受体激酶Tyro-Axl-Mer （TAM）家族的一员，调节小胶质/巨噬细胞的多种生理特征。然而，其在TBI中调节先天免疫反应和小胶质/巨噬细胞M1/M2极化的功能尚未得到解决。本研究旨在评估Mer在TBI后调节小胶质细胞/巨噬细胞M1/M2极化和神经炎症中的作用。方法采用控制性皮质冲击（CCI）小鼠模型。脑室内注射Mer siRNA，静脉注射重组蛋白S （PS）进行干预。进行神经行为学评估、RT-PCR、Western blot、磁活化细胞分选、免疫组织化学和共聚焦显微镜分析、尼氏染色和Fluoro-Jade B染色、脑含水量测定和挫伤体积评估。结果smer表达上调，调控脑外伤急性期小胶质细胞/巨噬细胞M1/M2极化和神经炎症。在机制上，Mer激活了转录1 (STAT1)/细胞因子信号传导1/3抑制因子（SOCS1/3）通路的信号转导和激活因子。抑制Mer显著降低小胶质细胞/巨噬细胞m2样极化，增加m1样极化，加重脑损伤后继发性脑损伤和感觉运动缺陷。重组PS通过Mer激活对TBI小鼠产生有益作用。结论smer是小胶质细胞/巨噬细胞M1/M2极化和神经炎症的重要调节因子，可能是TBI治疗干预的潜在靶点。
BackgroundTraumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/macrophage activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial/macrophage physiology. However, its function in regulating the innate immune response and microglial/macrophage M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial/macrophage M1/M2 polarization and neuroinflammation following TBI.MethodsThe controlled cortical impact (CCI) mouse model was employed. Mer siRNA was intracerebroventricularly administered, and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, magnetic-activated cell sorting, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed.ResultsMer is upregulated and regulates microglial/macrophage M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial/macrophage M2-like polarization while increases M1-like polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation.ConclusionsMer is an important regulator of microglial/macrophage M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.
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DOI：
10.1016/j.jaci.2018.01.029
发表时间：
2018-12
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Felton JM;Lucas CD;Dorward DA;Duffin R;Kipari T;Vermeren S;Robb CT;MacLeod KG;Serrels B;Schwarze J;Haslett C;Dransfield I;Rossi AG
通讯作者：
Rossi AG
影响因子：
5.6
作者：
Chou A;Krukowski K;Morganti JM;Riparip LK;Rosi S
通讯作者：
Rosi S
影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
影响因子：
5.6
作者：
Batsaikhan, Buyandelger;Wang, Jing-Ya;Wang, Jia-Yi
通讯作者：
Wang, Jia-Yi
影响因子：
9.3
作者：
Katsumoto A;Miranda AS;Butovsky O;Teixeira AL;Ransohoff RM;Lamb BT
通讯作者：
Lamb BT