Intestinal host defense outcome is dictated by PGE₂ production during efferocytosis of infected cells.

Abstract

Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-β, PGE₂, and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-β, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic <i>Escherichia coli</i>-infected macrophages by dendritic cells triggers PGE₂ production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE₂ during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic <i>E. coli</i>-infected cells by dendritic cells promoted high levels of PGE₂, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal <i>Citrobacter rodentium</i> infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against <i>C. rodentium</i> compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense.