{"doi":"10.1093/lifemeta/loae011","title":"Interleukin-10 suppresses lipid metabolism-mediated intestinal inflammation","abstract":"In a recent paper published in Nature, York et al. reported that the anti-inflammatory cytokine interleukin (IL)-10 regulates sphingolipid metabolism to limit NF-κB-mediated inflammation. Deletion of Il10 in mice, or genetic mutation of IL10 in humans, predisposes to inflammatory bowel disease, which may be overcome by restoring homeostatic sphingolipid metabolism The host response to infection is orchestrated by broad-ranging defense systems including rapid inflammation to target and neutralize invading pathogens, followed by a resolution phase to limit host damage. Key components of the inflammatory milieu include cytokines, which are heterogenous signaling proteins that trigger or dampen activation of immune pathways—a primary host defense mechanism—to combat the offending pathogen. A rapid return to homeostasis upon pathogen clearance is critical to avoid a pathological overamplification of this host-derived inflammatory response, which may drive inflammatory diseases, such as inflammatory bowel disease (IBD). One of the best-studied anti-inflammatory cytokine families is the interleukin-10 (IL-10) superfamily—a group of highly pleiotropic cytokines and their associated receptors—which can act via activation of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, a central component in host defense during infection or injury [1]. The IL-10 superfamily of immune mediators includes the IL-20 subfamily (comprising IL-19, IL-22, and other cytokines) and type III interferons (IFNλ1−4 in humans), which have been implicated in regulating gut homeostasis [2, 3]. IL-10 itself is critical for suppressing excessive activation of the immune response during infection, limiting host damage. A prime example of this is the severe and early-onset IBD that develops in mice [4] and humans [5] lacking functional IL10 or IL10RA/IL10RB (encoding the IL-10 receptor) genes, highlighting the protective role that IL-10 plays in maintaining intestinal homeostasis. The precise mechanism by which IL-10 exerts its anti-inflammatory functions is hitherto unknown. Nevertheless, IL-10 signaling in macrophages—an innate immune cell type that is important in attacking invading pathogens and mounting the host response to infections—has been shown to protect against colitis development [6, 7]. In a recent study published in Nature, York et al. [8] reported that IL-10 reduces intestinal inflammation in mice by tightly regulating lipid metabolism in macrophages (Fig. 1). A well-characterized feature of inflammatory macrophages is the crosstalk between macrophage metabolism and innate immune pathways, a process termed immunometabolism, and the authors found that downstream of Toll-like receptor TLR2 (a pattern recognition receptor for gram-positive bacteria including Staphylococcus aureus) activation, Il10-knockout (KO) mouse macrophages and mice exhibit alterations in their lipid compositions compared with wild-type (WT) counterparts. Il10 deficiency resulted in altered expression of components of sphingolipid biosynthesis—which is critical for cell membrane formation—via upregulation of the de novo ceramide synthesis pathway leading to the accumulation of ceramides and a decrease in sphingomyelins. IL-10 drives the synthesis of monounsaturated fatty acids (MUFAs) in macrophages to limit the production of proinflammatory very long chain (VLC) ceramides to regulate sphingolipid metabolism, maintaining homeostasis. However, in mice or humans with IL-10 signaling deficiency, IL-10-mediated MUFA production is abrogated, facilitating the accumulation of proinflammatory VLC ceramides that disrupts sphingolipid metabolism. This can result in prolonged NF-κB activation, driving the detrimental and proinflammatory phenotype associated with IBD. Figure was made with BioRender. York et al. next assessed whether ceramide accumulation might explain the proinflammatory phenotype which is characteristic of Il10-KO macrophages. They found that ex","journal":"Life Metabolism","year":2024,"id":454293,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.944,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":245464,"name":"Ivan Zanoni","orcid":"0000-0002-3423-7474","position":1,"is_corresponding":false},{"id":1014970,"name":"Tristram A.J. 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