Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity

Authors: XI, RANHUI - Monell Chemical Senses Center; MONTAGUE, JULIA - Monell Chemical Senses Center; LIN, XIAOLI - Monell Chemical Senses Center; LU, CHANYI - Monell Chemical Senses Center; LEI, WEIWEI - Monell Chemical Senses Center; TANAKA, KEISUKE - Tokyo University Of Agriculture & Technology; ZHANG, YALI - Monell Chemical Senses Center; XU, XIN - Sichuan University; ZHENG, XIN - Sichuan University; ZHOU, XUEDONG - Sichuan University; Urban, Joseph; IWATSUKI, KEN - Tokyo University Of Agriculture & Technology; MARGOLSKEE, ROBERT - Monell Chemical Senses Center; MATSUMOTO, ICHIRO - Monell Chemical Senses Center; TIZZANO, MARCO - Monell Chemical Senses Center; LI, JIYAO - Sichuan University; JIANG, PEIHUA - Monell Chemical Senses Center

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/9/2021
Publication Date: 7/27/2021
Citation: Xi, R., Montague, J., Lin, X., Lu, C., Lei, W., Tanaka, K., Zhang, Y., Xu, X., Zheng, X., Zhou, X., Urban Jr, J.F., Iwatsuki, K., Margolskee, R.F., Matsumoto, I., Tizzano, M., Li, J., Jiang, P. 2021. Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity. Proceedings of the National Academy of Sciences (PNAS). 118(30). Article e2026307118. https://doi.org/10.1073/pnas.2026307118.
DOI: https://doi.org/10.1073/pnas.2026307118

Interpretive Summary: Gastrointestinal nematode parasitic worm infections negatively affect the health and productivity of both infected humans and livestock. These infections also contribute to changes in the intestinal microbiome and the metabolism of nutrients. Despite improved understanding of cellular and molecular events that determine immune responses in the gut that facilitate protection against worm infection, the mechanism of action is not well defined. This report describes a family of genes called the gasdermin C genes (Gsdmcs) that are regulated in intestinal epithelial cells by host immune proteins called type 2 cytokines. Overexpression of Gsdmc2 triggered cell death in gut epithelium during worm-induced type 2 immunity. Parasitic infection often leads to malnutrition and retarded growth of the infected host, and this may involve disruption of the epithelial cell surface regulated by gasdermin activity. This may provide a pharmaceutical target for treatment of similar disorders caused by infection or activators of type 2 immunity such as allergic responses. This information is important to scientists including those interested in parasitic infection, allergy and nutrition and provides research targets to improve the function of the intestine.

Technical Abstract: “Taste-like” intestinal tuft cells in the intestine trigger type 2 immunity in response to worm infection. The secretion of interleukin-13 (IL-13) from innate lymphoid cell type 2 (ILC2) cells represents a key step in the tuft cell–ILC2 cell–intestinal epithelial cell circuit that drives clearance of worms from the gut via type 2 immune responses. Hallmark features of type 2 responses include tissue remodeling, such as tuft and goblet cell expansion and villus atrophy, yet it remains unclear if additional molecular changes in the gut epithelium facilitate clearance of worms from the gut. Using gut organoids, we demonstrated that IL-4 and IL-13, two type 2 cytokines with similar function, not only induced the classical type 2 responses (e.g., tuft cell expansion) but also drastically upregulated expression of gasdermin C genes (Gsdmcs). Using an in vivo worm-induced type 2 immunity model, we confirmed the upregulation of Gsdmcs in Nippostrongylus brasiliensis–infected wild-type and genetically modified C57BL/6 mice. Consistent with gasdermin family members being principal effectors of pyroptosis, overexpression of Gsdmc2 in HEK293 cells triggered pyroptosis and lytic cell death. Moreover, in intestinal organoids treated with IL-4 or IL-13, or in wild-type mice infected with N. brasiliensis, lytic cell death increased, which may account for villus atrophy observed in worm-infected mice. Thus, we propose that the upregulated Gsdmcs family may be major effectors for type 2 responses in the gut and that Gsdmc-mediated pyroptosis may provide a conduit for release of antiparasitic factors from enterocytes to facilitate clearance of worms.