Trpv4 regulates Nlrp3 inflammasome via SIRT1/PGC-1α pathway in a cuprizone-induced mouse model of demyelination
Trpv4 regulates Nlrp3 inflammasome via SIRT1/PGC-1α pathway in a cuprizone-induced mouse model of demyelination
复制标题
Trpv 4通过SIRT 1/PGC-1α途径调节Cuprizone诱导的小鼠脱髓鞘模型中Nlrp 3炎性小体
DOI：
10.1016/j.expneurol.2020.113593
复制
发表时间：
2021-01-06
影响因子：
5.3
通讯作者：
Yao, Ruiqin
中科院分区：
文献类型：
--
作者：
Liu, Yanan;Fan, Hongbin;Yao, Ruiqin
越来越多的证据表明，在脱髓鞘疾病过程中，含有3个Nlrp3结构域的Nod样受体的炎性小体过度激活。已有研究表明，瞬时受体电位4型(TRPV4)被认为是一种多峰离子亲和性受体，在包括炎症在内的多种病理条件下发挥重要作用。本研究的目的是探讨TRPV4通道是否对脱髓鞘小鼠痂体内的Nlrp3炎症小体有调节作用。结果显示，CPZ可显著增加TRPV4的表达，激活Nlrp3炎症小体，降低PGC-1α的表达，降低线粒体功能。SiRNA介导的Nlrp3基因敲除抑制了胶质细胞的激活，减轻了脱髓鞘的程度。而siRNA抑制TRPV4可明显改善Nlrp3炎性小体的激活，恢复线粒体功能，降低ROS水平。同时，siRNA介导的TRPV4基因敲除也减轻了CPZ所致的胶质细胞激活、脱髓鞘和行为损伤。此外，免疫沉淀和赖氨酸乙酰化试验表明，Sirtuin1(SIRT1)介导了PGC-1α去乙酰化，参与了Nlrp3炎症体的激活。这些发现表明，TRPV4通过SIRT1/PGC-1α途径调节线粒体功能，从而在CPZ诱导的小鼠脱髓鞘过程中进一步触发Nlrp3炎症体激活。
Increasing evidence has demonstrated that the Nod-like receptor pyrin domain containing 3 (Nlrp3) inflammasome overactivated during demyelinating disorders. It has been implicated that transient receptor potential type 4 (Trpv4) is regarded as a polymodal ionotropic receptor that plays an important role in a multitude of pathological conditions, including inflammation. The aim of this study was to investigate whether the Trpv4 channel regulates Nlrp3 inflammasome in the corpus callosum of mice with demyelination. Our results showed that CPZ treatment significantly increased the expression of Trpv4, activated Nlrp3 inflammasome, reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and decreased mitochondrial function. siRNA-mediated Nlrp3 knockdown inhibited glial activation and alleviated demyelination. Whereas knockdown of Trpv4 by siRNA markedly ameliorated Nlrp3 inflammasome activation and restored mitochondrial function as well as reducing the level of reactive oxygen species (ROS). Meanwhile, glial activation, demyelination and behavioral impairment induced by CPZ were also alleviated by siRNA-mediated Trpv4 knockdown. Furthermore, immunoprecipitation and use of a lysine acetylation assay showed that Sirtuin1 (SIRT1) mediated the PGC-1 alpha deacetylation, which is involved in Nlrp3 inflammasome activation. These findings suggest that Trpv4 regulates mitochondrial function through the SIRT1/PGC-1 alpha pathway, which further trigger Nlrp3 inflammasome activation in the CPZ-induced demyelination in mice.