The nucleotide-binding oligomerization domain (NOD)-like receptors belong to the family of pattern recognition receptors (PRRs). NOD-like receptors play a role in regulation of innate immune response by recognition of both pathogen-associated molecular patterns that are engulfed during phagocytic process and danger-associated molecular patterns that are mainly byproducts of cell stress mediated response. NOD-like family pyrin domain containing 6 (NLRP6) is one of the 14 pyrin domain-containing receptors. NLRP6 is highly expressed by epithelial and goblet cells to regulate epithelial renewal and mucus production in mice and humans, but its function in T cells is rather unknown. Increased caspase-1 activation and cell death were observed in mouse Nlrp6-deficient T cells following adoptive transfer into Rag2-deficient mice, indicating that Nlrp6 deficiency in CD4 + T cells led to decreased survival.

Goblet cells are essential for maintaining intestinal health and for the defense against invasive bacterial infection. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. Here we found that epithelial Gpr35 plays a critical role in goblet cell function. Genetic deletion of Gpr35 in epithelial cells but not in from macrophages results in goblet cell depletion and dysbiosis, rendering these mice more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows how the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.

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