STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice
STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice
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DOI：
10.1172/jci.insight.131355
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发表时间：
2019-10-17
期刊：
影响因子：
8
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Cai, Wei;Dai, Xuejiao;Chen, Jun
通过脑驻留的小胶质细胞和/或浸润的巨噬细胞对死亡/垂死细胞的效率作用或吞噬清除作用有助于中风后炎症消退和脑稳态的恢复。在这里，我们确定的信号转导和转录激活因子6/辅酶1（STAT 6/Arg 1）信号转导轴作为一个潜在的新机制，协调小胶质细胞/巨噬细胞在缺血性脑反应。在中风小鼠模型和中风患者的缺血区域中的小胶质细胞/巨噬细胞中观察到STAT 6的活化。STAT 6缺陷导致死亡/垂死神经元的清除减少，小胶质细胞/巨噬细胞中的炎症基因签名增加，并在实验性中风后早期扩大梗死体积。所有这些病理变化最终导致脑组织损失增加，并加剧了长期功能缺陷。使用BM嵌合体的组合体内分析和使用小胶质细胞/巨噬细胞-神经元共培养物的体外实验证实，小胶质细胞和巨噬细胞中的STAT 6活化对于神经保护是必不可少的。将WT巨噬细胞连续转移到STAT 6-KO小鼠中减少了缺血区域中死亡神经元的积累并改善了脑梗死。此外，在STAT 6（-/-）小胶质细胞/巨噬细胞中Arg 1的表达减少是导致细胞增殖障碍和细胞形态丧失的原因。我们的研究表明，通过STAT 6/Arg 1调节小胶质细胞/巨噬细胞表型，加速炎症消退，并改善中风的结果。
Efferocytosis, or phagocytic clearance of dead/dying cells by brain-resident microglia and/or infiltrating macrophages, is instrumental for inflammation resolution and restoration of brain homeostasis after stroke. Here, we identify the signal transducer and activator of transcription 6/arginase1 (STAT6/Arg1) signaling axis as a potentially novel mechanism that orchestrates microglia/macrophage responses in the ischemic brain. Activation of STAT6 was observed in microglia/macrophages in the ischemic territory in a mouse model of stroke and in stroke patients. STAT6 deficiency resulted in reduced clearance of dead/dying neurons, increased inflammatory gene signature in microglia/macrophages, and enlarged infarct volume early after experimental stroke. All of these pathological changes culminated in an increased brain tissue loss and exacerbated long-term functional deficits. Combined in vivo analyses using BM chimeras and in vitro experiments using microglia/macrophage-neuron cocultures confirmed that STAT6 activation in both microglia and macrophages was essential for neuroprotection. Adoptive transfer of WT macrophages into STAT6-KO mice reduced accumulation of dead neurons in the ischemic territory and ameliorated brain infarction. Furthermore, decreased expression of Arg1 in STAT6(-/-) microglia/macrophages was responsible for impairments in efferocytosis and loss of antiinflammatory modality. Our study suggests that efferocytosis via STAT6/Arg1 modulates microglia/macrophage phenotype, accelerates inflammation resolution, and improves stroke outcomes.