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* Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada;
Inflammation and Immunology, Graduate School of Medical Science,
Department of Biomedical Safety Science, and
Molecular Gastroenterology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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 (M
) challenged with CLF. Using the construct, we confirmed that endothelial cell PECAM-1 does not play a role in PMN transendothelial migration. Although M activation (NF-
B nuclear binding) and function (keratinocyte-derived chemokine production) induced by CLF was diminished in PECAM-1–/– M, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Canadian Institutes of Health Research Grants MOP13668, MOP 81303, and MGC 12816.
2 Address correspondence and reprint requests to Dr. Peter R. Kvietys, Lawson Health Research Institute, 800 Commissioners Road East, Sixth Floor, Victoria Research Laboratories, London, Ontario, Canada N6A 4G5. E-mail address: peter.kvietys{at}lhsc.on.ca
3 Abbreviations used in this paper: TNBS, 2,4,6,-trinitrobenzine sulfonic acid; BM, bone marrow; CLF, colonic lavage fluid; Cl2MDP, dichloromethylene diphosphonate; EtOH, ethanol; IBD, inflammatory bowel disease; KC, keratinocyte-derived chemokine; KO, knockout; LIX, LPS-induced CXC chemokine; M, macrophage; MMEC, mesenteric microvessel endothelial cell; MPO, myeloperoxidase; PMN, polymorphonuclear neutrophil; WT, wild type.
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