Trpv4 regulates Nlrp3 inflammasome via SIRT1/PGC-1α pathway in a cuprizone-induced mouse model of demyelination

Exp Neurol. 2021 Mar:337:113593. doi: 10.1016/j.expneurol.2020.113593. Epub 2020 Dec 31.

Abstract

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.

Keywords: Acetylation; Demyelination; Inflammation; Mitochondria; Nlrp3; Trpv4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chelating Agents
  • Cognition Disorders / genetics
  • Cognition Disorders / psychology
  • Corpus Callosum / pathology
  • Cuprizone
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / genetics*
  • Demyelinating Diseases / psychology
  • Gene Knockdown Techniques
  • Inflammasomes*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
  • Neuroglia
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species
  • Sirtuin 1 / genetics*
  • TRPV Cation Channels / physiology*

Substances

  • Chelating Agents
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Cuprizone
  • Sirt1 protein, mouse
  • Sirtuin 1