IL-10 constrains sphingolipid metabolism to limit inflammation

Nature. 2024 Mar;627(8004):628-635. doi: 10.1038/s41586-024-07098-5. Epub 2024 Feb 21.

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.

MeSH terms

  • Animals
  • Ceramides / chemistry
  • Ceramides / metabolism
  • Fatty Acids, Unsaturated / biosynthesis
  • Fatty Acids, Unsaturated / metabolism
  • Homeostasis
  • Humans
  • Immunity, Innate
  • Inflammation* / genetics
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Interleukin-10* / deficiency
  • Interleukin-10* / genetics
  • Interleukin-10* / metabolism
  • Mice
  • Proto-Oncogene Proteins c-rel
  • Sphingolipids* / metabolism

Substances

  • Ceramides
  • CERS2 protein, human
  • Cers2 protein, mouse
  • Fatty Acids, Unsaturated
  • Interleukin-10
  • Proto-Oncogene Proteins c-rel
  • REL protein, human
  • Sphingolipids