PECAM-1 is expressed on endothelial cells and leukocytes. Its extracellular domain has been implicated in leukocyte diapedesis. In this study, we used PECAM-1(-/-) mice and relevant cells derived from them to assess the role of
PECAM-1 in an experimental model of acute colonic
inflammation with a predominant innate immune response, i.e., 2,4,6-trinitrobenzine
sulfonic acid (TNBS). Using chimeric approaches, we addressed the points of control exerted by
PECAM-1 along the macrophage-endothelial cell-polymorphonuclear neutrophil (PMN) axis. In vivo, TNBS-induced
colitis was ameliorated in PECAM-1(-/-) mice, an event attributed to
PECAM-1 on hematopoietic cells rather than to
PECAM-1 on endothelial cells. The in vivo innate immune response was mimicked in vitro by using a construct of the vascular-interstitial interface, i.e., PMN transendothelial migration was induced by colonic lavage fluid (CLF) from TNBS mice or macrophages (MPhi) challenged with CLF. Using the construct, we confirmed that endothelial cell
PECAM-1 does not play a role in PMN transendothelial migration. Although MPhi activation (
NF-kappaB nuclear binding) and function (keratinocyte-derived
chemokine production) induced by CLF was diminished in PECAM-1(-/-) MPhi, this did not affect their ability to promote PMN transendothelial migration. By contrast, PECAM-1(-/-) PMN did not adhere to or migrate across endothelial cell monolayers in response to CLF. Further, as compared with PECAM-1(+/+) PMN, PECAM-1(-/-) PMN were less effective in orientating their
CXCR2 receptors (polarization) in the direction of a chemotactic gradient. Collectively, our findings indicate that
PECAM-1 modulation of PMN function (at a step before diapedesis) most likely contributes to the
inflammation in a
colitis model with a strong innate immune component.