ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury
ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury
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DOI：
10.1523/jneurosci.3233-16.2017
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发表时间：
2017-05-03
影响因子：
5.3
通讯作者：
Hu, Xiaoming
中科院分区：
文献类型：
--
作者：
Yang, Yuanyuan;Liu, Huan;Hu, Xiaoming
ST 2是白细胞介素（IL）1受体家族的成员，其配体IL-33在免疫调节和炎症反应中起关键作用。本研究探讨了内源性IL-33/ST 2信号在缺血性脑损伤中的作用，并阐明了潜在的作用机制。短暂性大脑中动脉闭塞（tMCAO）60 min后，少突胶质细胞和星形胶质细胞中IL-33的表达迅速增加。ST 2受体缺陷会加剧tMCAO和远端永久性MCAO后3天的脑梗死。ST 2缺乏也加重了MCAO后7 d的神经功能缺损。相反，tMCAO后侧脑室输注IL-33可减轻脑梗死。流式细胞术分析表明，ST 2的表达水平高的小胶质细胞，这种表达后tMCAO显着增强。ST 2的缺失增强了小胶质细胞/巨噬细胞上M1极化标志物的表达，并削弱了tMCAO后M2极化标志物的表达。对各种类型的培养物和共培养系统的体外研究证实，IL-33/ST 2信号转导增强了IL-10和其他M2基因在原代小胶质细胞中的表达。ST 2在小胶质细胞上的激活导致保护性表型，其增强神经元对氧葡萄糖剥夺的存活。进一步的体外研究表明，IL-33激活的小胶质细胞释放IL-10，这对它们的神经保护作用至关重要。类似地，将IL-33脑室内输注到IL-10敲除小鼠中未能提供针对体内tMCAO的神经保护。这些结果为IL-33/ST 2轴作为免疫调节机制提供了新的线索，该机制可作为缺血性脑损伤进展的自然制动器。
ST2, a member of the interleukin (IL) 1 receptor family, and its ligand IL-33 play critical roles in immune regulation and inflammatory responses. This study explores the roles of endogenous IL-33/ST2 signaling in ischemic brain injury and elucidates the underlying mechanisms of action. The expression of IL-33 rapidly increased in oligodendrocytes and astrocytes after 60 min transient middle cerebral artery occlusion (tMCAO). ST2 receptor deficiency exacerbated brain infarction 3 d after tMCAO as well as distal permanent MCAO. ST2 deficiency also aggravated neurological deficitsupto7daftertMCAO. Conversely, intracerebroventricular infusions of IL-33 after tMCAO attenuated brain infarction. Flow cytometry analyses demonstrated high levels of ST2 expression on microglia, and this expression was dramatically enhanced after tMCAO. The absence of ST2 enhanced the expression of M1 polarization markers on microglia/macrophages, and impaired the expression of M2 polarization markers after tMCAO. In vitro studies on various types of cultures and coculture systems confirmed that IL-33/ST2 signaling potentiated expression of IL-10 and other M2 genes in primary microglia. The activation of ST2 on microglia led to a protective phenotype that enhanced neuronal survival against oxygen glucose deprivation. Further in vitro studies revealed that IL-33-activated microglia released IL-10, and that this was critical for their neuroprotective effects. Similarly, intracerebroventricular infusions of IL-33 into IL-10 knock-out mice failed to provide neuroprotection against tMCAO in vivo. These results shed new light on the IL-33/ST2 axis as an immune regulatory mechanism that serves as a natural brake on the progression of ischemic brain injury.