Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, 77555, USA.
Department of Gastroenterology, The Shanghai Tenth People's Hospital, 200072, Shanghai, China.
Nat Commun. 2020 Sep 8;11(1):4457. doi: 10.1038/s41467-020-18262-6.
Innate lymphoid cells (ILCs) and CD4 T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4 T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4 T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4 T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4 T cells and ILCs to maintain intestinal homeostasis.
先天淋巴细胞 (ILC) 和 CD4 T 细胞产生 IL-22，这对于肠道免疫至关重要。微生物群是肠道中产生 IL-22 的核心；然而，调节 CD4 T 细胞和 ILC 产生 IL-22 的因素尚不清楚。在这里，我们表明，微生物群衍生的短链脂肪酸 (SCFA) 通过 G 蛋白受体 41 (GPR41) 和抑制组蛋白去乙酰化酶 (HDAC) 促进 CD4 T 细胞和 ILC 产生 IL-22。SCFAs 通过促进芳香烃受体 (AhR) 和缺氧诱导因子 1α (HIF1α) 的表达来上调 IL-22 的产生，而 AhR 和 HIF1α 的表达受 mTOR 和 Stat3 的差异调节。HIF1α 直接结合 Il22 启动子，SCFAs 通过组蛋白修饰增加 HIF1α 与 Il22 启动子的结合。SCFA 补充增强了 IL-22 的产生，从而保护肠道免受炎症。SCFAs 促进人 CD4 T 细胞 IL-22 的产生。这些发现确立了 SCFAs 在诱导 CD4 T 细胞和 ILC 产生 IL-22 以维持肠道内稳态中的作用。
