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 - Funding Information:
We thank all members of the Medzhitov lab for discussions and D. M. Sabatini for helpful suggestions. We thank R. Flavell (Yale University) for Casp1-/- mice, D. Mizushima for Atg5flox/flox mice (Tokyo Medical and Dental University), H. Virgin (Washington University) for Atg5flox/flox LysM-Cre mice, L. Ellisen (Massachusetts General Hospital) for bone-marrow cells from Ddit4-/- mice, S. Kaech (Yale University) for the use of Seahorse Analyzer, M. Staron and P.-C. Ho for assistance with Seahorse assays, the Yale Stem Cell Center for RNA-seq, Y. Kong for RNA-seq analysis, N. Allen and I. Brodsky for retroviral vector pMSCV-NLRP3/IRES-GFP, and C. Annicelli and S. Cronin for animal care. All data reported in this manuscript are tabulated in the main paper and supplementary materials. This work was supported by Helmsley Charitable Trust, Blavatnik Family Foundation, Else Kröner-Fresenius-Stiftung, and grants from the NIH (R01 AI046688, DK071754, and CA157461 to R.M.). R.M. is an investigator of the Howard Hughes Medical Institute.
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 -