Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation
Por:
Cosin-Roger, J, Simmen, S, Melhem, H, Atrott, K, Frey-Wagner, I, Hausmann, M, de Valliere, C, Spalinger, M, Spielmann, P, Wenger, R, Zeitz, J, Vavricka, S, Rogler, G and Ruiz, P
Publicada:
24 jul 2017
Resumen:
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 a, 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-.kappa 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.
Filiaciones:
:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Simmen, S:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Melhem, H:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Atrott, K:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Frey-Wagner, I:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Hausmann, M:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
de Valliere, C:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Spalinger, M:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Spielmann, P:
Univ Zurich, Inst Physiol, Winterthurerstr 190, CH-8057 Zurich, Switzerland
Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, CH-8057 Zurich, Switzerland
Wenger, R:
Univ Zurich, Inst Physiol, Winterthurerstr 190, CH-8057 Zurich, Switzerland
Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, CH-8057 Zurich, Switzerland
Zeitz, J:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Vavricka, S:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Rogler, G:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, CH-8057 Zurich, Switzerland
Ruiz, P:
Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Green Published, Green Accepted, gold
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