Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation
| Autor: | Isabelle Frey-Wagner, Gerhard Rogler, Roland H. Wenger, Pedro A. Ruiz, Kirstin Atrott, Simona Simmen, Jesus Cosin-Roger, Marianne R. Spalinger, Patrick Spielmann, Jonas Zeitz, Stephan R. Vavricka, Cheryl de Valliere, Hassan Melhem, Martin Hausmann |
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| Přispěvatelé: | University of Zurich, Ruiz, Pedro A |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
General Physics and Astronomy Pyrin domain 10052 Institute of Physiology Mice 0302 clinical medicine Crohn Disease RNA Small Interfering Mice Knockout Multidisciplinary integumentary system TOR Serine-Threonine Kinases Dextran Sulfate Colitis 3100 General Physics and Astronomy Interleukin-10 10219 Clinic for Gastroenterology and Hepatology 030220 oncology & carcinogenesis 10076 Center for Integrative Human Physiology medicine.symptom Science Down-Regulation Inflammation 610 Medicine & health 1600 General Chemistry Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Downregulation and upregulation 1300 General Biochemistry Genetics and Molecular Biology NLR Family Pyrin Domain-Containing 3 Protein Autophagy medicine Animals Humans PI3K/AKT/mTOR pathway RPTOR General Chemistry Hypoxia (medical) medicine.disease 030104 developmental biology Gene Expression Regulation Immunology Cancer research 570 Life sciences biology Colitis Ulcerative |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-13 (2017) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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