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 (PGD2). We test the hypothesis that tuft cell specific release of PGD2 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 PGD2 signaling. A subset of ILC3 express the PGD2 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.

Mechanisms of intestinal dysbiosis: new insights into tuft cell functions

“…Yet, opposite results regarding tuft cell-derived prostaglandin D2 have been reported in studies assessing the role of NAIP – NLRC4 inflammasome activation in tuft cells, and demonstrating that this pathway induces a prostaglandin D2 – ILC3 signaling pathway that contributes to bacterial pathogen clearance in the small intestine. 117 , 118 In addition, administration of N-C11-G to intestinal epithelial monolayers failed to induce a release of leukotrienes or ion influx showing that tuft cells were not activated by this ligand in this ex vivo context. 117 , 118 Thus, further studies are required to explore the recognition of pathogenic bacteria specific extracellular ligands by tuft cells.…”

“… 117 , 118 In addition, administration of N-C11-G to intestinal epithelial monolayers failed to induce a release of leukotrienes or ion influx showing that tuft cells were not activated by this ligand in this ex vivo context. 117 , 118 Thus, further studies are required to explore the recognition of pathogenic bacteria specific extracellular ligands by tuft cells. Noteworthily, microbes and parasites coexist in the same environment, interact and influence each other, and several studies reported an impact of helminth infection on microbiome composition.…”