TRPV1 mediates astrocyte activation and interleukin-1 release induced by hypoxic ischemia (HI)
TRPV1 mediates astrocyte activation and interleukin-1 release induced by hypoxic ischemia (HI)
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TRPV1 介导缺氧缺血 (HI) 诱导的星形胶质细胞活化和白细胞介素 1 释放
DOI：
10.1186/s12974-019-1487-3
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发表时间：
2019-05-29
影响因子：
9.3
通讯作者：
Peng, Bi-Wen
中科院分区：
文献类型：
--
作者：
Yang, Xing-Liang;Wang, Xin;Peng, Bi-Wen
背景缺氧缺血性脑病（HIE）是一种严重的出生并发症，在发达国家和发展中国家都有很高的发病率。从HIE中存活下来的儿童通常有严重的长期后遗症，包括脑瘫、癫痫和认知障碍。婴儿HIE的严重程度与IL-1表达的增加和星形胶质细胞的激活密切相关，这是由TRP家族中的一种非选择性阳离子通道TRPV1（瞬时受体电位香草样蛋白1）调节的。方法采用新生儿缺氧缺血（HI）和氧糖剥夺（OGD）模型模拟新生儿缺氧缺血（HIE）在体内和体外的发生。采用Western blot、q-PCR、免疫荧光等方法，观察培养的星形胶质细胞中胶质原纤维酸性蛋白（GFAP）、IL-1、Janus激酶2 （JAK2）、信号转导和转录激活因子3 （STAT3）的表达，以及核苷酸结合寡聚结构域（NOD）样受体pyrin结构域-containing protein 3 （NLRP3）炎症小体的活化。分别通过尼氏染色、2,3,5-三苯基四氮唑一水合物（TTC）染色和神经行为测试（地向反射、悬崖厌恶反应和握力测试）评估脑萎缩、梗死面积和神经行为障碍。结果新生儿HI和OGD刺激后星形胶质细胞过度活化。TRPV1 KO小鼠星形胶质细胞活化数量、IL-1表达水平、脑萎缩、梗死面积缩小均下调。星形胶质细胞TRPV1缺乏通过降低JAK2和STAT3的磷酸化来减弱GFAP和IL-1的表达。同时，通过抑制NLRP3炎性体的激活，TRPV1缺乏症星形胶质细胞中IL-1的释放明显减少。此外，新生儿hi诱导的神经行为障碍在TRPV1 KO小鼠中得到显著改善。结论strpv1主要通过JAK2-STAT3信号通路和NLRP3炎性小体的激活促进星形胶质细胞的激活和星形胶质细胞源性IL-1的释放。我们的研究结果为新生儿HIE引起的TRPV1介导的脑损伤和神经行为障碍提供了机制见解，并可能确定星形细胞TRPV1作为治疗亚急性期（24小时）HIE的新治疗靶点。
BackgroundHypoxic-ischemic encephalopathy (HIE) is a serious birth complication with high incidence in both advanced and developing countries. Children surviving from HIE often have severe long-term sequela including cerebral palsy, epilepsy, and cognitive disabilities. The severity of HIE in infants is tightly associated with increased IL-1 expression and astrocyte activation which was regulated by transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel in the TRP family.MethodsNeonatal hypoxic ischemia (HI) and oxygen-glucose deprivation (OGD) were used to simulate HIE in vivo and in vitro. Primarily cultured astrocytes were used for investigating the expression of glial fibrillary acidic protein (GFAP), IL-1, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and activation of the nucleotide-binding, oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome by using Western blot, q-PCR, and immunofluorescence. Brain atrophy, infarct size, and neurobehavioral disorders were evaluated by Nissl staining, 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and neurobehavioral tests (geotaxis reflex, cliff aversion reaction, and grip test) individually.ResultsAstrocytes were overactivated after neonatal HI and OGD challenge. The number of activated astrocytes, the expression level of IL-1, brain atrophy, and shrinking infarct size were all downregulated in TRPV1 KO mice. TRPV1 deficiency in astrocytes attenuated the expression of GFAP and IL-1 by reducing phosphorylation of JAK2 and STAT3. Meanwhile, IL-1 release was significantly reduced in TRPV1 deficiency astrocytes by inhibiting activation of NLRP3 inflammasome. Additionally, neonatal HI-induced neurobehavioral disorders were significantly improved in the TRPV1 KO mice.ConclusionsTRPV1 promotes activation of astrocytes and release of astrocyte-derived IL-1 mainly via JAK2-STAT3 signaling and activation of the NLRP3 inflammasome. Our findings provide mechanistic insights into TRPV1-mediated brain damage and neurobehavioral disorders caused by neonatal HI and potentially identify astrocytic TRPV1 as a novel therapeutic target for treating HIE in the subacute stages (24h).