RT Journal Article
SR Electronic
T1 Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 310110
DO 10.1101/310110
A1 Marija S. Nadjsombati
A1 John W. McGinty
A1 Miranda R. Lyons-Cohen
A1 Joshua L. Pollack
A1 G.A. Nagana Gowda
A1 David J. Erle
A1 Richard M. Locksley
A1 Daniel Raftery
A1 Jakob von Moltke
YR 2018
UL http://biorxiv.org/content/early/2018/04/29/310110.abstract
AB Initiation 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 helminth Nippostrongylus brasiliensis secretes succinate as a metabolite, and sensing of both succinate and N. brasiliensis requires 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.