Macrophage HIF-2α suppresses NLRP3 inflammasome activation and alleviates insulin resistance

Cell Rep. 2021 Aug 24;36(8):109607. doi: 10.1016/j.celrep.2021.109607.

Abstract

The interrelation between hypoxia and immune response has pivotal roles in the pathogenesis of chronic metabolic diseases. However, the role of macrophage HIF-2α in NLRP3 inflammasome activation remains unclear. Here, we show that deficiency of HIF-2α in macrophages results in excessive activation of the NLRP3 inflammasome in a manner dependent on CPT1A-mediated enhancement of fatty acid oxidation (FAO). Mechanistically, HIF-2α binds directly to the Cpt1a promoter and is involved in the regulation of H3K27me3 methylation during NLRP3 inflammasome activation. Myeloid-specific Hif2α knockout mice exhibit exacerbated insulin resistance and increased activation of NLRP3 inflammasome in macrophages. Overexpression of the Hif2α gene or stabilization of the protein by FG-4592 ameliorates insulin resistance and reduces NLRP3 inflammasome activation in macrophages. Taken together, our results suggest that macrophage HIF-2α inhibits FAO-mediated activation of the NLRP3 inflammasome and alleviates insulin resistance.

Keywords: Cpt1a; EPAS1; FG-4592; H3K27me3; NLRP3 inflammasome; fatty acid oxidation; hypoxia inducible factor 2; insulin resistance; macrophage; methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Humans
  • Inflammasomes / metabolism*
  • Insulin Resistance / physiology*
  • Lipid Metabolism / physiology
  • Macrophages / metabolism*
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • endothelial PAS domain-containing protein 1