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

By W. Ip, N. Hoshi, D. Shouval, S. Snapper, R. Medzhitov. Science, 2017

1,236 citations recorded by the source corpus.

An interleukin controls a metabolic switch in macrophages that inhibits a signaling pathway, thereby suppressing intestinal inflammation. A way to switch off IBD Inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease are associated with defective interleukin-10 (IL-10) signaling. Although IL-10 plays an essential role in the control and resolution of inflammation, the mechanisms responsible for its anti-inflammatory actions remain unclear. Ip et al. show that in response to inflammation, IL-10 controls cellular metabolism in macrophages by inducing the mTOR inhibitor DDIT4 and preventing glucose uptake (see the Perspective by Kabat and Pearce). In mouse models and patient samples, defective IL-10 promoted accumulation of damaged macrophages and exacerbated inflammatory signals. Targeting mTORC1 thus might help to treat IBD and related disorders. Science, this issue p. 513; see also p. 488 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.

Subfields: Genetics, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e772d86206f3d6080da9254ea3312954e1c09c45

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Citations in the corpus

Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. (2019, background): “This is consistent with the well-described ability of IL-10 to induce an anti-inflammatory macrophage phenotype (Moore et al., 2001), an activity that has recently been shown to involve metabolic reprogramming (Ip et al., 2017).”
Genome-wide enhancer maps link risk variants to disease genes (2021, background): “Notably, changes in Δ ψ m have been previously linked to inflammatory responses in macrophages 41 , suggesting a path by which tuning PPIF expression could affect IBD risk.”
Autophagy in inflammation, infection, and immunometabolism (2021, background): “For example, the anti-inflammatory cytokine IL-10 inhibits macrophage-intrinsic mTOR and glycolysis, promotes oxphos, and induces mitophagy to cull dysfunctional mitochondria and reduce inflammatory stimulation by mitochondrial DAMPs (Ip et al., 2017).”