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Cell. 2018 Jul 12;174(2):271-284.e14. doi: 10.1016/j.cell.2018.05.014. Epub 2018 Jun 7.

A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling.

Author information

1
Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA 94143, USA.
2
Department of Microbiology & Immunology, University of California San Francisco (UCSF), San Francisco, CA 94143, USA.
3
Research Diets, Inc., New Brunswick, NJ 08901, USA.
4
Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA 94143, USA; Department of Microbiology & Immunology, University of California San Francisco (UCSF), San Francisco, CA 94143, USA; Howard Hughes Medical Institute, UCSF. Electronic address: richard.locksley@ucsf.edu.

Abstract

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.

KEYWORDS:

A20; IL-25; ILC2s; TRPM5; Tritrichomonas; concomitant immunity; helminths; succinate; succinate receptor; tuft cells

PMID:
29887373
PMCID:
PMC6046262
DOI:
10.1016/j.cell.2018.05.014
[Indexed for MEDLINE]
Free PMC Article

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