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

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.

Rapamycin combined with MCC950 to treat multiple sclerosis in experimental autoimmune encephalomyelitis

“…Research suggests that autophagy is involved in the regulation of the inflammatory reaction process, preventing potential danger and resisting harmful stimuli. 11 Research has shown that inhibition of mTOR could suppress NLRP3 inflammasome activation. It plays an important role in regulating cell growth and the inflammatory response of CNS mediated by microglia.…”

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Abnormal basal autophagy can lead to various human diseases including cancer, neurodegenerative disorders, autoimmunity disease and inflammation (12)(13)(14)(15). Autophagy can be induced in response to several stressors including: nutrient deprivation, chemotherapeutics, hypoxia, pathogen infection and endoplasmic reticulum stress (16)(17)(18).…”

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

“…18,19 A vast amount of preclinical investigations indicates that pharmacologic targeting of HIF hydroxylases is a novel treatment option for many other diseases, ranging from inflammatory bowel disease over ischemic heart conditions to kidney inflammation and fibrosis. 18,[21][22][23][24] However, the underlying molecular mechanisms of the tissue-protective effect of hydroxylase inhibition are still not well understood. In preclinical studies, different hydroxylase inhibitors have been used, but their selectivity and possible HIF-independent off-target effects in cells are incompletely known and have not been comprehensively compared to each other.…”