Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit
| Autor: | Joshua L. Pollack, Miranda R. Lyons-Cohen, G. A. Nagana Gowda, Richard M. Locksley, John W. McGinty, Jakob von Moltke, Daniel Raftery, David J. Erle, Marija S. Nadjsombati |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Innate immune system urogenital system Taste Transduction Pathway Biology urologic and male genital diseases Small intestine female genital diseases and pregnancy complications Type 2 immune response Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Immune system medicine TRPM5 Tuft cell Receptor 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/310110 |
| Popis: | SummaryInitiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminthNippostrongylus brasiliensissecretes succinate as a metabolite, and sensing of both succinate andN. brasiliensisrequires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases. |
| Databáze: | OpenAIRE |
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