IL-10 constrains sphingolipid metabolism to limit inflammation.
1. Nature. 2024 Mar;627(8004):628-635. doi: 10.1038/s41586-024-07098-5. Epub 2024 Feb 21. IL-10 constrains sphingolipid metabolism to limit inflammation. York AG(1)(2)(3), Skadow MH(4), Oh J(5)(6), Qu R(4)(7), Zhou QD(8), Hsieh WY(8), Mowel WK(4), Brewer JR(4), Kaffe E(4), Williams KJ(9)(10), Kluger Y(7), Smale ST(11)(8), Crawford JM(5)(6)(12), Bensinger SJ(13)(14), Flavell RA(15)(16). Author information: (1)Department of Immunobiology, Yale University, New Haven, CT, USA. AGYork@UW.edu. (2)Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. AGYork@UW.edu. (3)Department of Immunology, School of Medicine, University of Washington, Seattle, WA, USA. AGYork@UW.edu. (4)Department of Immunobiology, Yale University, New Haven, CT, USA. (5)Department of Chemistry, Yale University, New Haven, CT, USA. (6)Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA. (7)Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA. (8)Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA. (9)Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. (10)UCLA Lipidomics Laboratory, Los Angeles, CA, USA. (11)Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. (12)Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA. (13)Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA. SBensinger@mednet.ucla.edu. (14)UCLA Lipidomics Laboratory, Los Angeles, CA, USA. SBensinger@mednet.ucla.edu. (15)Department of Immunobiology, Yale University, New Haven, CT, USA. Richard.Flavell@yale.edu. (16)Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. Richard.Flavell@yale.edu. Update of bioRxiv. 2023 May 08:2023.05.07.539780. doi: 10.1101/2023.05.07.539780. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. 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 unclear2-5. 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. © 2024. The Author(s). DOI: 10.1038/s41586-024-07098-5 PMCID: PMC10954550 PMID: 38383790 [Indexed for MEDLINE] Conflict of interest statement: R.A.F. is an advisor to Glaxo Smith Kline. The other authors declare no competing interests.
