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
Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.
Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Nat Commun. 2017 Jul 24;8(1):98. doi: 10.1038/s41467-017-00213-3.
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.
缺氧可调节自噬以及含吡啉结构域的核苷酸结合寡聚化结构域受体（NLRP）3，这两种先天性免疫机制相互调节并与炎症性肠病相关。在此我们表明，缺氧通过调节自噬和雷帕霉素哺乳动物靶蛋白（mTOR）/NLRP3通路，改善结肠炎发展过程中的炎症。缺氧显著降低肿瘤坏死因子α、白细胞介素（IL）-6和NLRP3表达，并增加克罗恩病患者结肠活检组织以及葡聚糖硫酸钠处理的小鼠和Il-10小鼠样本中自噬蛋白p62 的周转。在体外，缺氧诱导的自噬可降低核因子κB信号传导和NLRP3表达。我们还确定NLRP3是mTOR的一种新结合伴侣。二甲基草酰甘氨酸介导的羟化酶抑制可改善小鼠结肠炎、下调NLRP3并促进自噬。我们认为，缺氧通过下调mTOR与NLRP3 的结合以及激活自噬来对抗炎症。缺氧和HIF-1α激活在结肠炎小鼠模型中具有保护作用，且后者可调节自噬。在此，科辛 - 罗杰等人表明，缺氧通过抑制mTOR/NLRP3通路和促进自噬，改善克罗恩病患者和小鼠结肠炎模型中的肠道炎症。
