IL-10 Targets Macrophage Metabolism

RESEARCH HIGHLIGHTS

Nature Reviews Immunology | Published online 26 May 2017; doi:10.1038/nri.2017.57

wild-type metabolic phenotype IMMUNE REGULATION could not be restored in ATG5‑ deficient BMDMs by the addition IL‑10 targets macrophage of exogenous IL‑10. Thus, the effect of IL‑10 on mitochondrial function is highly dependent on autophagy. metabolism Activation of the mechanistic target of rapamycin (mTOR) complex 1 Although macrophages are Il10–/– BMDMs had a lower (mTORC1) promotes glycolysis and known to be the main target cells maximal respiratory capacity than inhibits autophagy, and mTORC1 of the anti-inflammatory cytokine accumulation wild-type cells after LPS stimulation, is thus a key potential target for interleukin‑10 (IL‑10), little is known of which indicates that lack of IL‑10 the mitochondrial effects of IL‑10. about the mechanisms by which could result in reduced mitochondrial Il10–/– BMDMs — and BMDMs IL‑10 mediates its effects. Medzhitov dysfunctional fitness and hence a reduced OCR. lacking the transcription factor STAT3 and colleagues provide new evidence mitochondria The authors therefore investigated (which is activated downstream of that IL‑10 regulates the metabolic in Il10–/– whether the altered metabolic profile the IL‑10 receptor) — had increased –/– switch to glycolysis that occurs in BMDMs was of Il10 BMDMs also results from and prolonged mTORC1 activation macrophages that are activated abnormal mitochondrial function. after LPS stimulation compared with with lipopolysaccharide (LPS) and the result Il10–/– BMDMs had an increased mito- wild-type cells. Directly inhibiting prevents the accumulation of of impaired chondrial mass after LPS stimulation mTOR with rapamycin in LPS- dysfunctional mitochondria. mitophagy compared with wild-type BMDMs stimulated Il10–/– BMDMs resulted After LPS stimulation, Il10–/– due to the accumulation of dysfunc- in decreased accumulation of dys- bone marrow-derived macrophages tional mitochondria with loss of the functional mitochondria, decreased (BMDMs) had higher levels of mitochondrial membrane potential. ECAR and increased OCR. DDIT4 (a glycolysis and lower levels of oxida- This was associated with increased known negative regulator of mTOR) tive phosphorylation compared production of mitochondrial reactive was strongly induced by IL‑10 in a with wild-type BMDMs, as oxygen species (ROS). STAT3‑dependent manner during measured by a higher extracellular Further experiments showed that LPS stimulation, and Ddit4–/– BMDMs acidification rate (ECAR) and a this accumulation of dysfunctional had prolonged mTORC1 activation lower oxygen consumption rate mitochondria in Il10–/– BMDMs was during LPS stimulation, which could (OCR), respectively. In wild-type the result of impaired mitophagy (the not be reduced by exogenous IL‑10. BMDMs, IL‑10 inhibited glycolysis selective degradation of mitochondria The authors conclude that IL‑10 by downregulating the translocation by autophagy). Il10–/– BMDMs had inhibits mTORC1 signalling in a of glucose transporter 1 (GLUT1) significantly lower levels of autophagy STAT3–DDIT4‑dependent manner, from intracellular vesicles to the than control cells after LPS stimulation. which is required for the inhibition of cell surface. Furthermore, IL‑10 BMDMs lacking autophagy protein 5 glycolysis and the autophagic clearance inhibited the expression of glycolytic (ATG5) had a decreased OCR, of dysfunctional, ROS-producing pathway genes. similar to Il10–/– BMDMs, but the mitochondria. As mitochondrial ROS can function as an endogenous DDIT4 second signal for inflammasome expression activation, BMDMs lacking IL‑10, LPS STAT3 or DDIT4 had increased inflammasome-mediated caspase 1 TLR signalling cleavage and IL‑1β production after LPS stimulation as a result of mTOR IL-10 STAT3 decreased mitophagy. Therefore, the mTORC1 activation inhibition expression activation mTORC1‑mediated effects of IL‑10 on macrophage metabolism have Mitophagy Switch from oxidative Inhibition Inhibition of crucial anti-inflammatory roles. phosphorylation to glycolysis of GLUT1 glycolytic gene Kirsty Minton translocation expression ORIGINAL ARTICLE Ip, W. K. E. et al. Anti-inflammatory effect of IL‑10 mediated by Clearance of ROS- Glycolysis metabolic reprogramming of macrophages. producing mitochondria Science 356, 513–519 (2017) Macmillan Publishers Limited