Targeting cellular fatty acid synthesis limits T helper and innate lymphoid cell function during intestinal inflammation and infection
Targeting cellular fatty acid synthesis limits T helper and innate lymphoid cell function during intestinal inflammation and infection
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DOI：
10.1038/s41385-020-0285-7
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发表时间：
2020-04-30
影响因子：
8
通讯作者：
Lochner, Matthias
中科院分区：
文献类型：
--
作者：
Mamareli, Panagiota;Kruse, Friederike;Lochner, Matthias
CD 4（+）T细胞在肠道感染期间对保护性免疫应答起关键作用，但也与肠道炎症病理学的恶化有关。以前的研究表明，辅助性T细胞（Th）1和Th 17细胞依赖于从头脂肪酸（FA）的合成，为他们的发展和效应功能。在这里，我们报告了T细胞特异性靶向乙酰辅酶A羧化酶1（ACC 1），一个控制FA合成的主要检查点，通过限制CD 4（+）T细胞扩增和浸润到结肠炎和感染相关肠道炎症小鼠模型的固有层中，损害肠道Th 1和Th 17反应。重要的是，天然化合物soraphen A对ACC 1的药理学抑制反映了T细胞特异性靶向的抗炎作用，但也增强了对C.啮齿动物。进一步的分析显示，ROR γ t（+）先天淋巴细胞（ILC）中ACC 1的缺失，而不是树突状细胞或巨噬细胞，通过干扰IL-22的产生和肠屏障功能，降低了对感染的抵抗力。总之，我们的研究表明，ACC 1的药理学靶向作为T细胞驱动的肠道炎症反应的代谢免疫调节的有效方法，但也揭示了ACC 1介导的脂肪生成对ROR γ t（+）ILC功能的重要作用。
CD4(+) T cells contribute critically to a protective immune response during intestinal infections, but have also been implicated in the aggravation of intestinal inflammatory pathology. Previous studies suggested that T helper type (Th)1 and Th17 cells depend on de novo fatty acid (FA) synthesis for their development and effector function. Here, we report that T-cell-specific targeting of the enzyme acetyl-CoA carboxylase 1 (ACC1), a major checkpoint controlling FA synthesis, impaired intestinal Th1 and Th17 responses by limiting CD4(+) T-cell expansion and infiltration into the lamina propria in murine models of colitis and infection-associated intestinal inflammation. Importantly, pharmacological inhibition of ACC1 by the natural compound soraphen A mirrored the anti-inflammatory effects of T-cell-specific targeting, but also enhanced susceptibility toward infection with C. rodentium. Further analysis revealed that deletion of ACC1 in ROR gamma t(+) innate lymphoid cells (ILC), but not dendritic cells or macrophages, decreased resistance to infection by interfering with IL-22 production and intestinal barrier function. Together, our study suggests pharmacological targeting of ACC1 as an effective approach for metabolic immune modulation of T-cell-driven intestinal inflammatory responses, but also reveals an important role of ACC1-mediated lipogenesis for the function of ROR gamma t(+) ILC.