TIPE2, a Novel Regulator of Immunity, Protects against Experimental Stroke
TIPE2, a Novel Regulator of Immunity, Protects against Experimental Stroke
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TIPE2 是一种新型免疫调节剂，可预防实验性中风。
DOI：
10.1074/jbc.m112.348755
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发表时间：
2012-09-21
影响因子：
4.8
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Wei, Xinbing;Yi, Fan
伴随卒中的炎症反应被认为是继发性缺血性损伤的原因。TIPE 2是最近鉴定的维持免疫稳态的炎症负调节因子。然而，TIPE 2是否在脑中表达并有助于脑疾病的调节尚不清楚。本研究旨在探讨TIPE 2在脑缺血/再灌注损伤中的作用。使用TIPE-/-小鼠来评估TIPE 2是否在由大脑中动脉闭塞（MCAO）诱导的脑缺血/再灌注后提供神经保护，并且使用体外原代脑细胞培养物来研究TIPE 2的表达和调节。我们的研究结果表明，Tipe 2基因的基因消融显着增加了脑梗死体积和神经功能障碍的小鼠进行MCAO。流式细胞术分析显示TIPE 2（-/-）小鼠缺血半球中有更多的浸润性巨噬细胞、中性粒细胞和淋巴细胞。TIPE 2（-/-）小鼠脑MCAO后对炎性细胞因子和趋化因子的反应显著增加。我们进一步观察到，TIPE 2在脑缺血后的WT小鼠中高度诱导，并且主要在小胶质细胞/巨噬细胞中表达，但不在神经元和星形胶质细胞中表达。最后，我们发现TIPE 2表达的调节与NADPH氧化酶活性相关。这些发现首次证明TIPE 2参与了中风的发病机制，并表明TIPE 2在将炎症免疫反应与脑缺血后的特定条件联系起来的信号转导途径中起着重要作用。以TIPE 2为靶点可能成为脑卒中治疗的新策略。
The inflammatory responses accompanying stroke are recognized to contribute to secondary ischemic injury. TIPE2 is a very recently identified negative regulator of inflammation that maintains immune homeostasis. However, it is unknown whether TIPE2 is expressed in the brain and contributes to the regulation of cerebral diseases. In this study, we explored the potential roles of TIPE2 in cerebral ischemia/reperfusion injury. TIPE-/- mice were used to assess whether TIPE2 provides neuroprotection following cerebral ischemia/reperfusion induced by middle cerebral artery occlusion (MCAO), and in vitro primary cerebral cell cultures were used to investigate the expression and regulation of TIPE2. Our results show that genetic ablation of the Tipe2 gene significantly increased the cerebral volume of infarction and neurological dysfunction in mice subjected to MCAO. Flow cytometric analysis revealed more infiltrating macrophages, neutrophils, and lymphocytes in the ischemic hemisphere of TIPE2(-/-) mice. The responses to inflammatory cytokines and chemokines were significantly increased in TIPE2(-/-) mouse brain after MCAO. We further observed that TIPE2 was highly induced in WT mice after cerebral ischemia and was expressed mainly in microglia/macrophages, but not in neurons and astrocytes. Finally, we found that regulation of TIPE2 expression was associated with NADPH oxidase activity. These findings demonstrate, for the first time, that TIPE2 is involved in the pathogenesis of stroke and suggest that TIPE2 plays an essential role in a signal transduction pathway that links the inflammatory immune response to specific conditions after cerebral ischemia. Targeting TIPE2 may be a new therapeutic strategy for stroke treatment.