IL-10 constrains sphingolipid metabolism to limit inflammation

Autumn G. York (), Mathias H. Skadow, Joonseok Oh, Rihao Qu, Quan D. 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 () and Richard A. Flavell ()
Additional contact information
Autumn G. York: Yale University
Mathias H. Skadow: Yale University
Joonseok Oh: Yale University
Rihao Qu: Yale University
Quan D. Zhou: Immunology and Molecular Genetics, UCLA
Wei-Yuan Hsieh: Immunology and Molecular Genetics, UCLA
Walter K. Mowel: Yale University
J. Richard Brewer: Yale University
Eleanna Kaffe: Yale University
Kevin J. Williams: David Geffen School of Medicine, UCLA
Yuval Kluger: Yale University
Stephen T. Smale: Yale University
Jason M. Crawford: Yale University
Steven J. Bensinger: Immunology and Molecular Genetics, UCLA
Richard A. Flavell: Yale University

Nature, 2024, vol. 627, issue 8004, 628-635

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 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.

Date: 2024
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DOI: 10.1038/s41586-024-07098-5

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