IL-10 constrains sphingolipid metabolism to limit inflammation

作者：Autumn Gabrielle York, Mathias H. Skadow, Joonseok Oh, Rihao Qu, Quan Zhou, Wei-Yuan Hsieh, Walter K. Mowel, J. Richard Brewer, Eleanna Kaffe, Kevin J. Williams, Yuval Kluger, Stephen T. Smale, Jason M. Crawford, Steven J. Bensinger, Richard Anthony Flavell · 发表于：Nature · 年份：2024 · DOI：10.1038/s41586-024-07098-5 · 被引用次数：242 · 研究领域：Sphingolipid Metabolism and Signaling、Immune Cell Function and Interaction、Immune cells in cancer

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 immun...