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Nature ; 627(8004): 628-635, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38383790

RESUMO

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.


Assuntos
Inflamação , Interleucina-10 , Esfingolipídeos , Animais , Humanos , Camundongos , Ceramidas/química , Ceramidas/metabolismo , Ácidos Graxos Insaturados/biossíntese , Ácidos Graxos Insaturados/metabolismo , Homeostase , Imunidade Inata , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/deficiência , Interleucina-10/genética , Interleucina-10/metabolismo , Proteínas Proto-Oncogênicas c-rel , Esfingolipídeos/metabolismo
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