York, Autumn G. and Skadow, Mathias H. and Oh, Joonseok and Qu, Rihao and Zhou, Quan D. and Hsieh, Wei-Yuan and Mowel, Walter K. and Brewer, J. Richard and Kaffe, Eleanna and Williams, Kevin J. and Kluger, Yuval and Smale, Stephen T. and Crawford, Jason M. and Bensinger, Steven J. and Flavell, Richard A. (2024) IL-10 constrains sphingolipid metabolism to limit inflammation. Nature. ISSN 0028-0836
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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 unclear.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.
Item Type: | Article |
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Subjects: | Open Research Librarians > Multidisciplinary |
Depositing User: | Unnamed user with email support@open.researchlibrarians.com |
Date Deposited: | 22 Feb 2024 05:45 |
Last Modified: | 22 Feb 2024 05:45 |
URI: | http://stm.e4journal.com/id/eprint/2500 |