Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity
Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity
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DOI：
10.1016/j.immuni.2019.09.014
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发表时间：
2019-11-19
期刊：
影响因子：
32.4
通讯作者：
Garrett, Wendy S.
中科院分区：
文献类型：
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作者：
Chun, Eunyoung;Lavoie, Sydney;Garrett, Wendy S.
第三组先天淋巴样细胞(ILC3)感知环境信号，这些信号对肠道内稳态和宿主防御至关重要。然而，调节结肠ILC3的代谢物感应G蛋白偶联受体仍然知之甚少。我们发现，结肠ILC3s表达微生物代谢物感受器Ffar2，Ffar2激动剂促进ILC3的扩张和功能。ILC3s缺乏Ffar2可降低其原位增殖和ILC3来源的白介素22(IL-22)的产生。这导致肠上皮功能受损，其特征是粘液相关蛋白和抗菌肽的改变，并增加了对结肠损伤和细菌感染的易感性。Ffar2增加结肠淋巴组织中IL-22(+)、CCR6(+)ILC3的表达，并影响ILC3的丰度。Ffar2激动剂通过AKT和STAT3轴不同地激活AKT或ERK信号，增加ILC3来源的IL-22。我们的发现表明，Ffar2调节结肠ILC3的增殖和功能，他们发现了一条ILC3受体信号通路，调节肠道内稳态和病原体防御。
Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deficiency of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived interleukin-22 (IL-22) production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22(+) CCR6(+) ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings suggest that Ffar2 regulates colonic ILC3 proliferation and function, and they identify an ILC3-receptor signaling pathway modulating gut homeostasis and pathogen defense.