Navigation auf zora.uzh.ch

Search ZORA

ZORA (Zurich Open Repository and Archive)

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

Cosin-Roger, Jesus; Simmen, Simona; Melhem, Hassan; Atrott, Kirstin; Frey-Wagner, Isabelle; Hausmann, Martin; de Vallière, Cheryl; Spalinger, Marianne R; Spielmann, Patrick; Wenger, Roland H; Zeitz, Jonas; Vavricka, Stephan R; Rogler, Gerhard; Ruiz, Pedro A (2017). Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nature Communications, 8(1):98.

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.

Additional indexing

Contributors:M. Blattmann and S. Scharl for organizing and collecting human colon biopsies., M. Madanchi for his help in collecting the human subjects data., S. Lang for technical support, Zurich Integrative Rodent Physiology (ZIRP) core facility of hte UZH for ther support in the animal experiments
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Zurich Center for Integrative Human Physiology (ZIHP)
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Physical Sciences > General Chemistry
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Physical Sciences > General Physics and Astronomy
Language:English
Date:2017
Deposited On:23 Aug 2017 15:17
Last Modified:17 Oct 2024 01:37
Publisher:Nature Publishing Group
ISSN:2041-1723
Funders:Swiss Philanthropy Foundation, SNF (Grant 324730_138291), SNF (Grant 314730_153380), Swiss IBD Cohort (Grant 314730_153380), European Crohn's and Colitis Organisation (ECCO) Fellowship
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-017-00213-3
PubMed ID:28740109
Project Information:
  • Funder:
  • Grant ID:
  • Project Title: Swiss Philanthropy Foundation
  • Funder: SNSF
  • Grant ID:
  • Project Title: SNF (Grant 324730_138291)
  • Funder: SNSF
  • Grant ID:
  • Project Title: SNF (Grant 314730_153380)
  • Funder:
  • Grant ID:
  • Project Title: Swiss IBD Cohort (Grant 314730_153380)
  • Funder:
  • Grant ID:
  • Project Title: European Crohn's and Colitis Organisation (ECCO) Fellowship
Download PDF  'Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation'.
Preview
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

Metadata Export

Statistics

Citations

Dimensions.ai Metrics
220 citations in Web of Science®
239 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

136 downloads since deposited on 23 Aug 2017
10 downloads since 12 months
Detailed statistics

Authors, Affiliations, Collaborations

Similar Publications