IL-10 constrains sphingolipid metabolism to limit inflammation

• Published in: Nature (London) Vol. 627; no. 8004; pp. 628 - 635
• Main Authors: York, Autumn G., Skadow, Mathias H., Oh, Joonseok, Qu, Rihao, Zhou, Quan D., Hsieh, Wei-Yuan, Mowel, Walter K., Brewer, J. Richard, Kaffe, Eleanna, Williams, Kevin J., Kluger, Yuval, Smale, Stephen T., Crawford, Jason M., Bensinger, Steven J., Flavell, Richard A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.03.2024; Nature Publishing Group
• Subjects: 38; 38/91; 631/250/256/2515; 631/250/262/2106/2108; 631/250/347; 631/45/287/1196; 631/45/608; 64/60; 82; 82/1; 96; 96/21; 96/31; Accumulation; Animals; Cell activation; Ceramide; Ceramides - chemistry; Ceramides - metabolism; Cytokines; Desaturation; Fatty acids; Fatty Acids, Unsaturated - biosynthesis; Fatty Acids, Unsaturated - metabolism; Gene deletion; Gene expression; Homeostasis; Humanities and Social Sciences; Humans; Immune system; Immunity, Innate; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin 10; Interleukin-10 - deficiency; Interleukin-10 - genetics; Interleukin-10 - metabolism; Lipid metabolism; Lipids; Metabolic flux; Metabolism; Metabolites; Mice; multidisciplinary; Proto-Oncogene Proteins c-rel; Science; Science (multidisciplinary); Signal transduction; Sphingolipids - metabolism; Transcription factors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07098-5

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. IL-10 exerts its anti-inflammatory activity in macrophages by increasing the expression of enzymes that promote fatty acid desaturation and downstream regulation of the transcription factor REL.