Critical role for PGI2 in the regulation of IL-22 production by intestinal innate immune cells (P3191)

Abstract Our previous studies have shown that prostacyclin (PGI2) plays an important role in regulating mucosal inflammatory responses and the development of IL-17-producing innate T cells. Using mice lacking the PGI2 receptor, IP, we have investigated the role of this prostanoid in innate immune responses in the intestine. IL-22 belongs to the IL-10 family of cytokines and targets innate immune pathways due to the restricted expression of IL-22 receptors on innate cells critical to maintaining barrier function, such as epithelial cells. Our results revealed that IP receptor deficient mice (IP-/- mice) had a marked increase in intestinal IL-22 production by innate lymphoid cells, but a clear defect in IgA production. Importantly, the number of CD3-NKp46+ lymphoid cells was dramatically increased in the Peyer’s patch of IP-/- mice compared to wild-type animals and the cells produced high levels of IL-22 in response to IL-23 exposure. Concomitant with the enhanced IL-22 production, altered intestinal mucus production and reduced number of inter-follicular cells in the Peyer’s patch was observed in IP-/- mice compared to wild-type mice. Collectively, these results demonstrate that PGI2 plays a critical role in regulating IL-22 production and limiting NKp46+ lymphoid cell responses in the intestine. Since expression of IL-22 is induced in several human gut inflammatory conditions including Crohn’s disease, these findings may have implications in inflammatory bowel disease.