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IL-10 reprogramming of metabolism in macrophages through mitophagy

Inflammation is a protective mechanism in response to injury and infection, which works to isolate and eliminate foreign material from the body. However, when inflammation becomes uncontrolled and non-resolving, normal tissue can be damaged either through the immune system attacking ‘self’ or as a result of chronic tissue injury. To limit pathogenesis and allow for repair processes, immunoregulatory mechanisms exist. One such example is the anti-inflammatory cytokine IL-10; a master regulator of immunity, that limits the production and release of pro-inflammatory cytokines and chemokines by macrophages, and the expression of antigen presenting molecules. Dysregulation of IL-10 has been implicated with the development of many autoimmune disorders and is associated with increased immunopathology in response to infection. Deficiency of IL-10 or its receptor leads to inflammation of the intestine in mice, that is recapitulated in macrophage specific IL-10 mouse lines. Furthermore, genome-wide association studies (GWAS) have associated the IL-10 gene within the susceptibility locus for ulcerative colitis and inflammatory bowel disease (IBD), but the mechanisms by which IL-10 mediates its effects are unknown. A recent study by Ip et al. provide new evidence linking IL-10 in the control of macrophage function by its reprogramming of metabolic pathways to aid in the clearance of dysfunctional mitochondria, thereby inhibiting the pro-inflammatory response. The authors show that defective IL-10 signalling in macrophages in both mice and humans, results in IBD, through the accumulation of damaged mitochondria and dysregulated activation of the NLRP3 inflammasome. Several current studies have highlighted the crucial role of metabolic reprogramming in macrophage activation. This has been associated with mitochondrion reactive oxygen species (ROS) generation to promote a pro-inflammatory state and Lipopolysaccharide (LPS)-induced glycolytic flux in controlling IL-10induction via cell autonomous means to regulate macrophage nitric oxide (NO) production. Additional studies have shown alterations in the regulatory relationship between mitochondria and the microbiome is found in Crohns disease. The new findings by Ip et al., linking these processes together, highlight that IL-10 promotes the induction of mitophagy—the selective process of degradation of mitochondria by autophagy, suggesting that IL-10 plays a more direct role in maintaining mitochondrial integrity, which is important in preserving respiratory capacity. The inflammatory response can be influenced by metabolic reprogramming, that is initiated by activation of toll like receptors (TLR). In macrophages stimulated with LPS, a TLR4 ligand, aerobic glycolysis is activated, independent of mitochondrial oxidative phosphorylation. However, Ip and colleagues show IL-10 macrophages have altered metabolic profiles after stimulation with LPS; increased glycolysis, and further reduced oxidative phosphorylation in comparison to control macrophages. This is combined with increased mitochondrial mass a result of the failure of mitophagy. As a product of oxidative phosphorylation, damaged mitochondria produce an increased level of ROS that causes cell damage. Glucose and lipid metabolism is controlled by crucial metabolic pathways such as the activation of mammalian target of rapamycin complex 1 (mTORC1) that regulates autophagy, a process important for removing damaged proteins and organelles. Inhibition of TOR activation is known to induce autophagy. However, Ip et al., observed sustained mTORC1 signalling and consequently impaired autophagy in IL-10 macrophages, which was rescued with the addition Dr Jyoti Patel is British Heart Foundation, Centre of Research Excellence Intermediate Transition Fellow in Cardiovascular Science at the Radcliffe Department of Medicine at the University of Oxford. Her research is focused on downstream chemokine receptor regulation in leukocyte trafficking in the inflammatory and repair phase following myocardial infarction. Her work involves exploring the mechanisms that regulate leukocyte accumulation at inflammatory sites, which will help to identify novel therapeutic targets in MI and heart failure. She has won numerous research awards and is actively involved in public engagement for learning and scientific debate amongst the public, and mentorship to support junior post-doctoral scientists in training.