Zhou Kai, Zhong Qi, Wang Yan-Chun, Xiong Xiao-Yi, Meng Zhao-You, Zhao Ting, Zhu Wen-Yao, Liao Mao-Fan, Wu Li-Rong, Yang Yuan-Rui, Liu Juan, Duan Chun-Mei, Li Jie, Gong Qiu-Wen, Liu Liang, Yang Mei-Hua, Xiong Ao, Wang Jian, Yang Qing-Wu
1 Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
2 Basic Medical College, Zhengzhou University, Zhengzhou, China.
J Cereb Blood Flow Metab. 2017 Mar;37(3):967-979. doi: 10.1177/0271678X16648712. Epub 2016 Jul 20.
Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3-mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3β), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-β did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3β/PTEN axis.
由炎性细胞外周浸润介导的炎症在脑出血（ICH）所致继发性损伤中起重要作用。既往研究表明，调节性T淋巴细胞（Tregs）可能减轻ICH诱导的炎症，但导致ICH诱导的炎性损伤的确切机制仍不清楚。我们的结果显示，ICH后脑中Tregs数量增加。使用CD25抗体或Foxp3基因敲除小鼠诱导Tregs缺失会增加神经功能缺损评分（NDS）、炎性因子水平、血肿体积和神经元变性。同时，使用CD28超激动剂抗体增强Tregs可减轻炎性损伤。此外，Tregs耗竭使小胶质细胞/巨噬细胞极化转向M1表型，而增强Tregs则使这种转变转向M2表型。在体外，小胶质细胞与Tregs的transwell共培养模型表明，Tregs改变了小胶质细胞的极化，降低了MHC-II、IL-6和TNF-α的表达，并增加了CD206的表达。源自Tregs的IL-10通过增加糖原合酶激酶3β（GSK3β）的表达介导小胶质细胞极化，GSK3β使小胶质细胞中的磷酸酶和张力蛋白同源物（PTEN）磷酸化并使其失活，TGF-β不参与这种转变。因此，Tregs通过IL-10/GSK3β/PTEN轴调节小胶质细胞/巨噬细胞向M2表型极化，从而减轻ICH诱导的炎性损伤。
