1. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages
- Author
-
Dror S. Shouval, Ruslan Medzhitov, Scott B. Snapper, W. K. Eddie Ip, and Namiko Hoshi
- Subjects
0301 basic medicine ,Inflammasomes ,medicine.medical_treatment ,Interleukin-1beta ,Oxidative phosphorylation ,Biology ,Article ,Mice ,03 medical and health sciences ,NLR Family, Pyrin Domain-Containing 3 Protein ,Mitophagy ,medicine ,Animals ,Humans ,Receptors, Interleukin-10 ,PI3K/AKT/mTOR pathway ,Inflammation ,Multidisciplinary ,DDIT4 ,TOR Serine-Threonine Kinases ,Macrophages ,Inflammasome ,Macrophage Activation ,Colitis ,Inflammatory Bowel Diseases ,Mice, Mutant Strains ,Interleukin-10 ,Mitochondria ,Cell biology ,Intestines ,Disease Models, Animal ,Interleukin 10 ,030104 developmental biology ,Cytokine ,Immunology ,biology.protein ,Signal transduction ,Reactive Oxygen Species ,Signal Transduction ,Transcription Factors ,medicine.drug - Abstract
Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays a critical role in the control of immune responses. However, its mechanisms of action remain poorly understood. Here, we show that IL-10 opposes the switch to the metabolic program induced by inflammatory stimuli in macrophages. Specifically, we show that IL-10 inhibits lipopolysaccharide-induced glucose uptake and glycolysis and promotes oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian target of rapamycin (mTOR) activity through the induction of an mTOR inhibitor, DDIT4. Consequently, IL-10 promotes mitophagy that eliminates dysfunctional mitochondria characterized by low membrane potential and a high level of reactive oxygen species. In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease patients, and this results in dysregulated activation of the NLRP3 inflammasome and production of IL-1β.
- Published
- 2017
- Full Text
- View/download PDF