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Blood, 15 July 2005, Vol. 106, No. 2, pp. 584-592.
Prepublished online as a Blood First Edition Paper on April 5, 2005; DOI 10.1182/blood-2004-12-4942.
Previous Article | Next Article 
Submitted January 7, 2005
Accepted March 15, 2005
ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF- activated vascular endothelium under flow
Lin Yang, Richard M Froio, Tracey E Sciuto, Ann M Dvorak, Ronen Alon, and Francis W Luscinskas*
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Departments of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
* Corresponding author; email: fluscinskas{at}rics.bwh.harvard.edu.
In vivo, leukocyte transendothelial migration (TEM) occurs at endothelial cell junctions (paracellular) and non-junctional (transcellular) locations whereas in vitro models report TEM is mostly paracellular. The mechanisms that control the route of leukocyte TEM remain unknown. Here we tested the hypothesis that elevated ICAM-1 expression regulates the location of polymorphonuclear leukocyte (PMN) TEM. We used an in vitro flow model of TNF- activated human umbilical vein endothelium (HUVEC) or a HUVEC cell line transfected with ICAM-1GFP and live cell fluorescence microscopy to quantify the location of PMN adhesion and TEM. We observed robust transcellular TEM with TNF- activated HUVEC and ICAM-1GFP iHUVEC. In contrast, primary CD3+ T lymphocytes exclusively used a paracellular route. Endothelial ICAM-1 was identified as essential for both paracellular and transcellular PMN transmigration and interfering with ICAM-1 cytoplasmic tail function preferentially reduced transcellular TEM. We also found that ICAM-1 surface density and distribution as well as endothelial cell shape contributed to transcellular TEM. In summary, ICAM-1 promotes junctional and non-junctional TEM across inflamed vascular endothelium via distinct cytoplasmic tail associations.

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