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

Abstract

“Taste-like” tuft cells in the intestine trigger type 2 immunity in response to worm infection. The secretion of interleukin-13 (IL-13) from type 2 innate lymphoid cells (ILC2) represents a key step in the tuft cell–ILC2 cell–intestinal epithelial cell circuit that drives the 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 the clearance of worms from the gut. Using gut organoids, we demonstrated that IL-4 and IL-13, two type 2 cytokines with similar functions, not only induced the classical type 2 responses (e.g., tuft cell expansion) but also drastically up-regulated the expression of gasdermin C genes (Gsdmcs). Using an in vivo worm-induced type 2 immunity model, we confirmed the up-regulation of Gsdmcs in Nippostrongylus brasiliensis–infected wild-type C57BL/6 mice. Consistent with gasdermin family members being principal effectors of pyroptosis, overexpression of Gsdmc2 in human embryonic kidney 293 (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 up-regulated Gsdmc family may be major effectors for type 2 responses in the gut and that Gsdmc-mediated pyroptosis may provide a conduit for the release of antiparasitic factors from enterocytes to facilitate the clearance of worms.

Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon acute intestinal injury

“…GSDMs are critical effectors of pyroptosis, a form of inflammatory cell death (Kovacs and Miao 2017). Compared to other GSDMs, very little is known about the functions of GSDMC, and scattered reports have involved GSDMC in the lytic death of tumor cells (Hou, Zhao et al 2020, Zhang, Zhou et al 2021), or of enterocytes during helminth infections (Xi, Montague et al 2021). Of note, non-irradiated mice administered with rIFN-λ do not show upregulation of the GSDMC protein ( Figure S4A ), demonstrating that additional pathways associated with irradiation and/or tissue damage and repair regulate Gsdmc gene expression and/or protein synthesis.…”

Stem Cells From Human Exfoliated Deciduous Teeth Alleviate Liver Cirrhosis via Inhibition of Gasdermin D-Executed Hepatocyte Pyroptosis

“…GSDME is reported to promote inflammation and fibrosis in obstructive nephropathy ( 38 ). Recent studies demonstrate that the function of the gasdermin family still remains explored, and there are pathways of pyroptosis waiting to be discovered ( 39 – 41 ). The exact role of the GSDM family members and pathways of pyroptosis in liver cirrhosis still needs further exploration.…”

Tuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces

“…Calcium release then induces TRPM5 to open, causing cellular depolarization that stimulates IL-25 release—pushing the classical tuft cell–ILC2 loop into action [ 47 ]. Downstream mucosal type 2 immune responses aid in mounting a classical “weep and sweep” response and gasdermin C–mediated activation that drive helminth expulsion [ 23 , 108 ].…”