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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.

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.

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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 > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2017
Deposited On:23 Aug 2017 15:17
Last Modified:29 Aug 2017 15:34
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
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-017-00213-3
PubMed ID:28740109

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