美国耶鲁大学Richard A. Flavell，美国加州大学Steven J. Bensinger和美国华盛顿大学Autumn G. York共同合作，近期取得重要工作进展。他们研究提出，IL-10抑制鞘脂代谢以限制炎症。相关研究成果2024年2月21日在线发表于《自然》杂志上。
据介绍，白细胞介素-10（IL-10）是一种关键的抗炎细胞因子，可以限制先天免疫细胞类型的免疫细胞激活和细胞因子产生。IL-10信号传导的丧失会导致人类和小鼠患上危及生命的炎症性肠病。然而，IL-10信号转导抑制炎症的确切机制尚不清楚。
研究人员发现饱和超长链（VLC）神经酰胺的增加对炎症基因表达的增加至关重要，这是IL-10缺乏的标志。因此，负责VLC神经酰胺产生的神经酰胺合成酶2（由Cers2编码）的基因缺失限制了体外和体内与IL-10缺乏相关的炎症基因表达程序的恶化。饱和VLC神经酰胺的积累受到通过从头单不饱和脂肪酸合成途径的代谢通量减少的调节。向缺乏IL-10信号传导的细胞恢复单不饱和脂肪酸的可用性限制了饱和VLC神经酰胺的产生和相关的炎症。从机制上讲，研究人员发现VLC神经酰胺介导的持续炎症在很大程度上取决于免疫调节转录因子REL的持续活性。
总之，这些数据表明，IL-10驱动的脂肪酸去饱和程序重新连接了VLC神经酰胺的积累和REL的异常激活。这些研究支持先天免疫细胞中的脂肪酸稳态是控制病理性炎症的关键调节节点的观点，并表明VLC稳态的“代谢校正”可能是使由缺乏IL-10引起的失调炎症正常化的重要策略。
附：英文原文
Title: IL-10 constrains sphingolipid metabolism to limit inflammation
Author: York, Autumn G., Skadow, Mathias H., Oh, Joonseok, Qu, Rihao, Zhou, Quan D., Hsieh, Wei-Yuan, Mowel, Walter K., Brewer, J. Richard, Kaffe, Eleanna, Williams, Kevin J., Kluger, Yuval, Smale, Stephen T., Crawford, Jason M., Bensinger, Steven J., Flavell, Richard A.
Issue&Volume: 2024-02-21
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 unclear2,3,4,5. 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.
DOI: 10.1038/s41586-024-07098-5
Source: https://www.nature.com/articles/s41586-024-07098-5
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
