PGE2 signaling triggers CD31-independent transendothelial migration in vitro and in vivo.

Abstract

Genetic deletion or antibody blockade of platelet endothelial cell adhesion molecule-1 (CD31, PECAM) 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 pro-inflammatory lipid mediator that binds four E prostanoid receptors (EP1-4). 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 (PMNs) and peripheral blood mononuclear cells (PBMCs) despite a TEM blockade with anti-CD31. This pro-transmigratory effect could be blocked with the EP1 antagonist, SC-51089, or with transient receptor potential canonical 6 (TRPC6) antagonist, BI-749327. 17-phenyl trinor PGE₂, an agonist of EP1 and EP3, also restored transmigration of PMNs 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 TRPC6.