Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation

Nat Commun. 2017 Jul 24;8(1):98. doi: 10.1038/s41467-017-00213-3.

Abstract

Hypoxia regulates autophagy and nucleotide-binding oligomerization domain receptor, pyrin domain containing (NLRP)3, two innate immune mechanisms linked by mutual regulation and associated to IBD. Here we show that hypoxia ameliorates inflammation during the development of colitis by modulating autophagy and mammalian target of rapamycin (mTOR)/NLRP3 pathway. Hypoxia significantly reduces tumor necrosis factor α, interleukin (IL)-6 and NLRP3 expression, and increases the turnover of the autophagy protein p62 in colon biopsies of Crohn's disease patients, and in samples from dextran sulfate sodium-treated mice and Il-10 -/- mice. In vitro, NF-κB signaling and NLRP3 expression are reduced through hypoxia-induced autophagy. We also identify NLRP3 as a novel binding partner of mTOR. Dimethyloxalylglycine-mediated hydroxylase inhibition ameliorates colitis in mice, downregulates NLRP3 and promotes autophagy. We suggest that hypoxia counteracts inflammation through the downregulation of the binding of mTOR and NLRP3 and activation of autophagy.Hypoxia and HIF-1α activation are protective in mouse models of colitis, and the latter regulates autophagy. Here Cosin-Roger et al. show that hypoxia ameliorates intestinal inflammation in Crohn's patients and murine colitis models by inhibiting mTOR/NLRP3 pathway and promoting autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology
  • Colitis / chemically induced
  • Colitis, Ulcerative / metabolism*
  • Crohn Disease / metabolism*
  • Dextran Sulfate / toxicity
  • Down-Regulation
  • Gene Expression Regulation / physiology
  • Humans
  • Inflammation / metabolism*
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • RNA, Small Interfering
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • IL10 protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • RNA, Small Interfering
  • Interleukin-10
  • Dextran Sulfate
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse