The contributions of NAIP/NLRC4 inflammasome activation in Tuft cells to host barrier defense and immunity.

Abstract

Abstract The small intestine is a key interface between host cells and potentially pathogenic agents, and as such has developed an array of host defense mechanisms to mitigate disease. The role of the epithelium in preventing systemic disease is becoming more appreciated, however the function of a subset of epithelial cells, the tuft cells, outside of parasitic sensing remains unclear. Tuft cells express all of the NAIP/NLRC4 inflammasome components, suggesting that tuft cells have the ability to recognize bacterial pathogens. The NAIP/NLRC4 inflammasome is a multi-protein complex that forms when bacterial flagellin or type III secretion systems are detected in the cytosol of the host cell, leading to induction of pyroptosis. The exact contributions of NAIP/NLRC4 inflammasome activation in tuft cells towards host barrier defense and immunity are not known. Data generated by my lab demonstrates that activation of the NAIP/NLRC4 inflammasome in tuft cells facilitates robust release of prostaglandin D2. The specific function of prostaglandin D2 release after NAIP/NLRC4 inflammasome activation in not currently known. However, it has been demonstrated that a subset of innate lymphoid cells (ILCs), ILC3s express the receptor for prostaglandin D2 and after activation, secrete IL-17 and IL-22, key cytokines that promote host defense against bacterial infections. We find that after specific activation of NAIP/NLRC4 inflammasome in tuft cells, IL-22 protein is increased in the small intestine. These findings support our hypothesis that tuft cells are not simply parasitic sensors but contribute to host barrier defense and immunity against bacterial pathogens.