Enteric tuft cell inflammasome activation drives NKp46⁺ILC3 IL22 via PGD₂ and inhibits Salmonella

To distinguish pathogens from commensals, the intestinal epithelium employs cytosolic innate immune sensors. Activation of the NAIP–NLRC4 inflammasome initiates extrusion of infected intestinal epithelial cells (IEC) upon cytosolic bacterial sensing. We previously reported that activation of the inflammasome in tuft cells, which are primarily known for their role in parasitic infections, leads to the release of prostaglandin D2 (PGD₂). We observe that NAIP–NLRC4 inflammasome activation in tuft cells leads to an antibacterial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD₂ signaling. A NKp46⁺ subset of ILC3 expresses the PGD₂ receptor CRTH2 and is the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control of Salmonella Typhimurium in the distal small intestine. However, tuft cells in the cecum and colon are dispensable for antibacterial immunity. These data support that intestinal tuft cells can also induce antibacterial responses, possibly in a tissue-specific manner.