Prostaglandin E2 Signaling Triggers CD31-Independent Transendothelial Migration in Vitro and in Vivo.

Genetic deletion or antibody blockade of platelet endothelial cell adhesion molecule-1 (PECAM; CD31) inhibits transendothelial migration (TEM) of leukocytes in all mouse strains studied except C57BL/6. A prior publication showed that this phenotype maps to a single 35.8-Mb locus on mouse chromosome 2, that contains the genes Ptgs1, Ptges, and Ptges2, which encode key enzymes involved in the prostaglandin E2 (PGE2) synthesis pathway. PGE2 is a proinflammatory lipid mediator that binds four E prostanoid receptors (EPs 1 to 4). It was hypothesized that PGE2 signaling supports TEM via a CD31-independent mechanism. In vitro TEM assays demonstrate that PGE2 or 16,16-dimethyl PGE2 can restore transmigration of polymorphonuclear leukocytes and peripheral blood mononuclear cells despite a TEM blockade with anti-CD31. This protransmigratory effect could be blocked with the EP1 antagonist, SC-51089, or with transient receptor potential canonical 6 antagonist, BI-749327. 17-Phenyl trinor PGE2, an agonist of EP1 and EP3, also restored transmigration of polymorphonuclear leukocytes blocked with anti-CD31. In vivo, PGE2 overcame an anti-CD31 blockade when administered to FVB/n mice in thioglycolate peritonitis or croton oil dermatitis models, whereas blocking EP1 with SC-51089 decreased TEM in C57BL/6 pecam1-/- mice. The findings support earlier data that identified PGE2 as a candidate inducer of CD31-independent TEM, and pinpoint EP1 as the receptor that relays that signal to activate transient receptor potential canonical 6.