NAIP—NLRC4 inflammasome activation in tuft cells contributes to host defense against bacteria

Abstract The small intestinal epithelium is exposed to various microbes, and intestinal epithelial cells (IECs) have developed an array of host defense mechanisms to distinguish commensals from pathogenic microbes and initiate an immune response against the later. NAIP—NLRC4 inflammasome induced-pyroptosis, which is activated when bacterial flagellin or type III secretion systems are detected in the cytosol of the host cell, is one such mechanism. Activation of NAIP—NLRC4 induces extrusion of IECs and release of the inflammatory mediators prostaglandin E2 and IL-18. Work on epithelial inflammasome activation thus far has not delineated if different subtypes of IECs have specific roles in the ensuing immune response. Tuft cells are a rare subset of IEC that is primarily known for its role in sensing parasites, and it is unknown whether they are involved in promoting antibacterial host responses. Here we show that upon activation of the NAIP—NLRC4 inflammasome specifically in tuft cells, they uniquely among IECs release prostaglandin D2, and within the small intestine, tissue IL-22 increases. NLRC4 expression only in tuft cells leads to better control of Salmonella Typhimurium compared to NLRC4 null controls. Taken together, these data suggest that NAIP— NLRC4 inflammasome activation in tuft cells leads to lipid mediator induced downstream inflammatory responses that are complementary to signaling pathways that are activated by other IEC subsets. Understanding how NAIP—NLRC4 activation in different epithelial subsets affects downstream inflammatory responses will inform on the different signaling pathways that synergize together to mount pathogen specific host defense mechanisms.