IL-10 constrains sphingolipid metabolism to limit inflammation.

Autor: York AG; Department of Immunobiology, Yale University, New Haven, CT, USA. AGYork@UW.edu.; Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. AGYork@UW.edu.; Department of Immunology, School of Medicine, University of Washington, Seattle, WA, USA. AGYork@UW.edu., Skadow MH; Department of Immunobiology, Yale University, New Haven, CT, USA., Oh J; Department of Chemistry, Yale University, New Haven, CT, USA.; Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA., Qu R; Department of Immunobiology, Yale University, New Haven, CT, USA.; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA., Zhou QD; Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA., Hsieh WY; Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA., Mowel WK; Department of Immunobiology, Yale University, New Haven, CT, USA., Brewer JR; Department of Immunobiology, Yale University, New Haven, CT, USA., Kaffe E; Department of Immunobiology, Yale University, New Haven, CT, USA., Williams KJ; Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; UCLA Lipidomics Laboratory, Los Angeles, CA, USA., Kluger Y; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA., Smale ST; Howard Hughes Medical Institute, Yale University, New Haven, CT, USA.; Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA., Crawford JM; Department of Chemistry, Yale University, New Haven, CT, USA.; Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA.; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA., Bensinger SJ; Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA. SBensinger@mednet.ucla.edu.; UCLA Lipidomics Laboratory, Los Angeles, CA, USA. SBensinger@mednet.ucla.edu., Flavell RA; Department of Immunobiology, Yale University, New Haven, CT, USA. Richard.Flavell@yale.edu.; Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. Richard.Flavell@yale.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Mar; Vol. 627 (8004), pp. 628-635. Date of Electronic Publication: 2024 Feb 21.
DOI: 10.1038/s41586-024-07098-5
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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