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

Dejani NN, Orlando AB, Niño VE, Penteado LA, Verdan FF, Bazzano JMR, Codo AC, Salina ACG, Saraiva AC, Avelar MR, Spolidorio LC, Serezani CH, Medeiros AI
Proc Natl Acad Sci U S A. 2018 115 (36): E8469-E8478

PMID: 30127026 · PMCID: PMC6130380 · DOI:10.1073/pnas.1722016115

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, PGE, 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 -infected macrophages by dendritic cells triggers PGE production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic -infected cells by dendritic cells promoted high levels of PGE, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against 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.

MeSH Terms (11)

Animals Citrobacter rodentium Colitis Dendritic Cells Dinoprostone Enterobacteriaceae Infections Female Intestines Macrophages Mice Receptors, Prostaglandin E, EP4 Subtype

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