Trpv4 regulates Nlrp3 inflammasome via SIRT1/PGC-1α pathway in a cuprizone-induced mouse model of demyelination
| Autor: | Yanan Liu, Zhian Liu, Hongbin Fan, Ruiqin Yao, Xinyu Li, Xiuxiang Wu, Meiying Liu, Xuebin Qu, Jing Liu |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine TRPV4 Inflammasomes TRPV Cation Channels Mitochondrion Pyrin domain Corpus Callosum Cuprizone Mice 03 medical and health sciences Transient receptor potential channel 0302 clinical medicine Sirtuin 1 Developmental Neuroscience NLR Family Pyrin Domain-Containing 3 Protein Coactivator medicine Animals RNA Small Interfering Receptor Chelating Agents Gene knockdown integumentary system Chemistry Inflammasome Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mitochondria Cell biology Mice Inbred C57BL 030104 developmental biology Neurology Gene Knockdown Techniques Cognition Disorders Reactive Oxygen Species Neuroglia 030217 neurology & neurosurgery Demyelinating Diseases medicine.drug |
| Zdroj: | Experimental Neurology. 337:113593 |
| ISSN: | 0014-4886 |
| DOI: | 10.1016/j.expneurol.2020.113593 |
| Popis: | 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 1α (PGC-1α) 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-1α deacetylation, which is involved in Nlrp3 inflammasome activation. These findings suggest that Trpv4 regulates mitochondrial function through the SIRT1/PGC-1α pathway, which further trigger Nlrp3 inflammasome activation in the CPZ-induced demyelination in mice. |
| Databáze: | OpenAIRE |
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