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A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling
Open accessAbstract
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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“Tissue and circulating succinate is also elevated in other chronic inflammatory settings such as models of diet-induced obesity8.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [8]
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Metadata
- Authors
- Schneider, C., O’Leary, C. E., von Moltke, J., Liang, H.-E., Ang, Q. Y., Turnbaugh, P. J., Radhakrishnan, S., Pellizzon, M., Ma, A., & Locksley, R. M.
- Affiliations
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Locksley, Richard M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 174
- Issue
- 2
- Pages
- 271-284.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6046262
- OpenAlex
- W2807333794
- Cited by
- 478
- References
- 54
- Citations by year
- 2026: 56 · 2025: 69 · 2024: 60 · 2023: 57 · 2022: 58 · 2021: 60 · 2020: 47 · 2019: 49 · 2018: 20
- FWCI
- 18.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (AI26918, AI30663, HL128903, HL122593)
- Howard Hughes Medical Institute
- Sandler Asthma Basic Research Center at the UCSF
- Swiss National Science Foundation (P2EZP3_162266, P300PA_171591)
- Nadia’s Gift Foundation Innovator
- Damon Runyon Cancer Research Foundation (DRR-42-16)
- UCSF Program for Breakthrough Biomedical Research
- Sandler Foundation
- Searle Scholars Program (SSP-2016-1352)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- tuft cells, ILC2, IL-25, A20, succinic acid, acetate, GPR91, TRPM5, Tritrichomonas, intestinal helminths, concomitant immunity, dietary polysaccharides, weaning
- MeSH terms
- Tumor Necrosis Factor alpha-Induced Protein 3, Acetates, Animals, Dietary Fiber, Energy Metabolism, Epithelial Cells, Interleukins, Intestinal Mucosa, Intestine, Small, Mice, Inbred C57BL, Mice, Transgenic, Plasmids, Tritrichomonas, Receptors, Interleukin, Succinic Acid, Receptors, G-Protein-Coupled, TRPM Cation Channels, Mice, Receptors, Interleukin-17, Microbiota
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