TY - JOUR
T1 - Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages
AU - Ip, W. K.Eddie
AU - Hoshi, Namiko
AU - Shouval, Dror S.
AU - Snapper, Scott
AU - Medzhitov, Ruslan
N1 - Publisher Copyright:
© 2017, American Association for the Advancement of Science. All rights reserved.
PY - 2017/5/5
Y1 - 2017/5/5
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aal3535
DO - 10.1126/science.aal3535
M3 - Article
C2 - 28473584
AN - SCOPUS:85018784717
SN - 0036-8075
VL - 356
SP - 513
EP - 519
JO - Science
JF - Science
IS - 6337
ER -