Location: Diet, Genomics and Immunology LaboratoryTitle: Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine
|LEI, WEIWEI - Monell Chemical Senses Center|
|REN, WENWEN - Monell Chemical Senses Center|
|OHMOTO, MAKOTO - Monell Chemical Senses Center|
|MATSUMOTO, ICHIRO - Monell Chemical Senses Center|
|MARGOLSKEE, ROBERT - Monell Chemical Senses Center|
|JIANG, PEIHUA - Monell Chemical Senses Center|
Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/7/2018
Publication Date: 5/22/2018
Citation: Lei, W., Ren, W., Ohmoto, M., Urban Jr, J.F., Matsumoto, I., Margolskee, R.F., Jiang, P. 2018. Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine. Proceedings of the National Academy of Sciences. (21):5552-5557. https://doi.org/10.1073/pnas.1720758115.
Interpretive Summary: Tuft cells in the intestine are known to act as sentinels to detect worm and bacterial infections and they have been shown to express taste-signaling elements. This study showed that the receptor for a dietary short chain fatty acid, succinate, was expressed in tuft cells. Feeding succinate or perturbing the intestinal microbiome to produce succinate activated tuft cells to produce protein messenger molecules that help control certain types of infection. One of the molecules produced by tufts cells is IL-25 which when given to obese mice fed a high-fat diet results in loss in body weight and adipose tissue mass, and improved glucose metabolism. Given that succinate is able to trigger IL-25-mediated responses it was speculated that dietary succinate may have similar metabolic effects for improved glucose metabolism and reduced adipose tissue. Whether the effect of succinate on the IL-25 biology also contributes to the beneficial effects of succinate on glucose homeostasis remains to be determined, but the study did suggest that a specific link between dietary succinate and tuft cell activation could contribute to changes in intestinal homeostasis. This information is important to research scientists trying to understand the activator of protective immunity and how those responses are also linked to metabolic activity that regulates body mass and health.
Technical Abstract: The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that the succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate-Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here, we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells, but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft-cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1-/-)showed diminished immune responses to treatment with polyethylene glycol and streptomycin, that are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucrn1 is required for microbiota-induced but not a generalized worm-induced type 2 immunity.