A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling.
A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling.
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DOI：
10.1016/j.cell.2018.05.014
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发表时间：
2018-07-12
期刊：
影响因子：
64.5
通讯作者：
Locksley RM
中科院分区：
文献类型：
--
作者：
Schneider C;O'Leary CE;von Moltke J;Liang HE;Ang QY;Turnbaugh PJ;Radhakrishnan S;Pellizzon M;Ma A;Locksley RM
小肠簇状细胞-ILC 2回路通过簇状细胞化学传感样传感和IL-25介导的固有层ILC 2的激活来介导上皮对肠道蠕虫和原生生物的反应。小肠ILC 2组成型表达IL-25受体，其由A20（Tnfaip 3）负调节。ILC 2中的A20缺陷自发地触发回路，并且出乎意料地促进适应性小肠延长和重塑。回路激活发生在断奶时，并且通过使小鼠允许三毛滴虫定殖的膳食多糖来实现，从而导致乙酸盐和琥珀酸盐（原生生物氢酶体的代谢物）的管腔积累。簇细胞表达GPR 91，琥珀酸受体，饮食琥珀酸，但不是乙酸，激活ILC 2通过簇，TRPM 5，和IL-25依赖性途径。也由寄生蠕虫诱导，回路激活和小肠重塑损害新蠕虫的侵染，与伴随免疫的现象一致。我们描述了一个代谢传感电路，可能已经发展到促进互惠互利的反应，管腔病理共生体。小肠中共生定殖原生生物产生的琥珀酸盐激活簇细胞-ILC 2回路，导致适应性重塑，增加表面积吸收和预防其他感染。
The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20-deficiency in ILC2s spontaneously triggers the circuit, and, unexpectedly, promotes adaptive small intestinal lengthening and remodeling. Circuit activation occurs upon weaning, and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome. Tuft cells express GPR91, the succinate receptor, and dietary succinate, but not acetate, activates ILC2s via a tuft-, TRPM5-, and IL-25-dependent pathway. Also induced by parasitic helminths, circuit activation and small intestinal remodeling impairs infestation by new helminths, consistent with the phenomenon of concomitant immunity. We describe a metabolic sensing circuit that may have evolved to facilitate mutualistic responses to luminal pathosymbionts. Succinate produced by mutualistic colonizing protists in the small intestine activates a tuft cell - ILC2 circuit, leading to adaptive remodeling that increases surface area absorption and prevention of other infections.
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