NAIP—NLRC4 Inflammasome Activation in Tuft Cells Activates a PGD2–ILC3 Signaling Circuit that Protects Against Enteric Infection

Abstract Intestinal epithelial cells (IEC) use innate sensing pathways to distinguish pathogens from commensals. One such pathway, the NAIP—NLRC4 inflammasome, initiates extrusion of infected IEC and mediator release upon cytosolic bacterial sensing. Tuft cells are primarily known for their function in anti-parasite immunity. We previously reported that activation of the inflammasome in tuft cells leads to release of prostaglandin D2 (PGD 2 ). We test the hypothesis that tuft cell specific release of PGD 2 after inflammasome activation initiates antibacterial responses. NAIP—NLRC4 inflammasome activation in tuft cells leads to a type 3 antimicrobial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD 2 signaling. A subset of ILC3 express the PGD 2 receptor CRTH2 and we show them as the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control of Salmonella Typhimurium. These data support that intestinal tuft cells can also induce antibacterial responses. Summary PGD 2 release after NAIP—NLRC4 inflammasome activation in tuft cells signals onto ILC3s and mediates host defense mechanisms against Salmonella Typhimurium within the small intestine. Tuft cells therefore not only promote immune reactions against parasites, but also bacteria.