{"doi":"10.1038/s41586-024-07098-5","title":"IL-10 constrains sphingolipid metabolism to limit inflammation","abstract":"Abstract Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types 1 . Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice—however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear 2–5 . Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2 ), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that ‘metabolic correction’ of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.","journal":"Nature","year":2024,"id":416197,"datarank":0.8182981673036553,"base_score":5.455321115357702,"endowment":5.455321115357702,"self_citation_contribution":0.8182981673036553,"citation_network_contribution":0.0,"self_endowment_contribution":0.8182981673036553,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":233,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"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":80239,"name":"Mathias Skadow","orcid":"0000-0001-6646-5810","position":1,"is_corresponding":false},{"id":393375,"name":"Joonseok Oh","orcid":"0000-0002-7616-1949","position":2,"is_corresponding":false},{"id":246262,"name":"Rihao Qu","orcid":"0000-0002-8258-8287","position":3,"is_corresponding":false},{"id":254559,"name":"Quan Zhou","orcid":"0000-0002-0184-4884","position":4,"is_corresponding":false},{"id":256924,"name":"Wei-Yuan Hsieh","orcid":null,"position":5,"is_corresponding":false},{"id":1199217,"name":"Walter K. Mowel","orcid":"0000-0003-2393-4300","position":6,"is_corresponding":false},{"id":553175,"name":"J. Richard Brewer","orcid":null,"position":7,"is_corresponding":false},{"id":956568,"name":"Eleanna Kaffe","orcid":"0000-0002-7761-4460","position":8,"is_corresponding":false},{"id":254560,"name":"Kevin J. Williams","orcid":"0000-0001-8091-7924","position":9,"is_corresponding":false},{"id":69468,"name":"Yuval Kluger","orcid":"0000-0002-3035-071X","position":10,"is_corresponding":false},{"id":254568,"name":"Stephen T. Smale","orcid":"0000-0002-9835-6907","position":11,"is_corresponding":false},{"id":304470,"name":"Jason M. Crawford","orcid":"0000-0002-7583-1242","position":12,"is_corresponding":false},{"id":254569,"name":"Steven J. Bensinger","orcid":"0000-0002-9657-4206","position":13,"is_corresponding":false},{"id":80236,"name":"Richard A. Flavell","orcid":"0000-0003-4461-0778","position":14,"is_corresponding":false},{"id":80225,"name":"Autumn G. York","orcid":"0000-0002-0331-043X","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:56:20.964471Z","pmid":"38383790","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}