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

被引：334

作者：

Cosin-Roger, Jesus ^{[1
]}

Simmen, Simona ^{[1
]}

Melhem, Hassan ^{[1
]}

Atrott, Kirstin ^{[1
]}

Frey-Wagner, Isabelle ^{[1
]}

Hausmann, Martin ^{[1
]}

de Valliere, Cheryl ^{[1
]}

Spalinger, Marianne R. ^{[1
]}

Spielmann, Patrick ^{[2
,3
]}

Wenger, Roland H. ^{[2
,3
]}

Zeitz, Jonas ^{[1
]}

Vavricka, Stephan R. ^{[1
]}

Rogler, Gerhard ^{[1
,3
]}

Ruiz, Pedro A. ^{[1
]}

机构：

[1] Univ Zurich, Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland

[2] Univ Zurich, Inst Physiol, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[3] Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, CH-8057 Zurich, Switzerland

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

瑞士国家科学基金会;

关键词：

GENOME-WIDE ASSOCIATION; HIGH-ALTITUDE JOURNEYS; INDUCIBLE FACTOR-I; BOWEL-DISEASE; CROHNS-DISEASE; HIF HYDROXYLASES; GENE-EXPRESSION; CANCER CELLS; KAPPA-B; COLITIS;

D O I：

10.1038/s41467-017-00213-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：13

共 69 条

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