title: Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier.
abstract: The extravasation of CD4(+) effector/memory T cells (TEM cells) across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM-1 and ICAM-2 are essential for CD4(+) TEM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM-1 in determining the cellular route of CD4(+) TEM -cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions, inducing high levels of endothelial ICAM-1, promoted rapid initiation of transcellular diapedesis of CD4(+) T cells across the BBB, while intermediate levels of endothelial ICAM-1 favored paracellular CD4(+) T-cell diapedesis. Importantly, the route of T-cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly, a low number of CD4(+) TEM cells was found to cross the inflamed BBB in the absence of endothelial ICAM-1 and ICAM-2 via an obviously alternatively regulated transcellular pathway. In vivo, this translated to the development of ameliorated EAE in ICAM-1(null) //ICAM-2(-/-) C57BL/6J mice. Taken together, our study demonstrates that cell surface levels of endothelial ICAM-1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T-cell diapedesis across the BBB.
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Abadier
authors.forename: Neda
authors.initials: N
authors.lastname: Haghayegh Jahromi
authors.forename: Ludmila
authors.initials: L
authors.lastname: Cardoso Alves
authors.forename: Rémy
authors.initials: R
authors.lastname: Boscacci
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Scott
authors.initials: S
authors.lastname: Barnum
authors.forename: Urban
authors.initials: U
authors.lastname: Deutsch
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology; D005260:Female; D007156:Immunologic Memory / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C480027:ICAM-2 protein, mouse; D008565:Membrane Proteins; D018799:Intercellular Adhesion Molecule-1
keywords: Blood-brain barrier; CD4+ effector/memory T (TEM) cells; Diapedesis; EAE; ICAM-1