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A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling
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...
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Published in: | Cell 2018-07, Vol.174 (2), p.271-284.e14 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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.
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•Tuft cell IL-25 and IL-25R+ ILC2s drive A20-regulated small bowel adaptability•Circuit activation and small bowel hypertrophy maintain systemic energy balance•Succinate, a Tritrichomonas metabolite, triggers tuft cell chemosensation and IL-25•Circuit activation impedes new helminth infection and enables concomitant immunity
Succinate produced by mutualistic colonizing protozoa activates a small intestinal tuft cell-ILC2 circuit, leading to adaptive remodeling that facilitates energy homeostasis and infection resistance in the host and a reproductive niche for the pathosymbiont. |
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ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2018.05.014 |