Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages

作者：Ip, W. K. Eddie; Hoshi, Namiko; Shouval, Dror S.; Snapper, Scott; Medzhitov, Ruslan^*

来源：Science, 2017, 356(6337): 513-519.

DOI：10.1126/science.aal3535

• MECHANISTIC TARGET
• DENDRITIC CELLS
• GROWTH-CONTROL
• MTORC1
• AUTOPHAGY
• INNATE
• INHIBITION
• COMMITMENT
• ACTIVATION
• IL-1-BETA

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-1 beta.

• 出版日期2017-5-5