Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis.
An active involvement of blood-brain barrier endothelial cell basement membranes in development of inflammatory lesions in the central nervous system (CNS) has not been considered to date. Here we investigated the molecular composition and possible function of the extracellular matrix encountered by extravasating T lymphocytes during experimental autoimmune encephalomyelitis (EAE). Endothelial basement membranes contained laminin 8 (alpha4beta1gamma1) and/or 10 (alpha5beta1gamma1) and their expression was influenced by proinflammatory cytokines or angiostatic agents. T cells emigrating into the CNS during EAE encountered two biochemically distinct basement membranes, the endothelial (containing laminins 8 and 10) and the parenchymal (containing laminins 1 and 2) basement membranes. However, inflammatory cuffs occurred exclusively around endothelial basement membranes containing laminin 8, whereas in the presence of laminin 10 no infiltration was detectable. In vitro assays using encephalitogenic T cell lines revealed adhesion to laminins 8 and 10, whereas binding to laminins 1 and 2 could not be induced. Downregulation of integrin alpha6 on cerebral endothelium at sites of T cell infiltration, plus a high turnover of laminin 8 at these sites, suggested two possible roles for laminin 8 in the endothelial basement membrane: one at the level of the endothelial cells resulting in reduced adhesion and, thereby, increased penetrability of the monolayer; and secondly at the level of the T cells providing direct signals to the transmigrating cells.
Sixt
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Interdisciplinary Center for Clinical Research (IZKF), Nikolaus Fiebiger Center, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany.
Engelhardt
B
B
Pausch
F
F
Hallmann
R
R
Wendler
O
O
Sorokin
L M
LM
D000818:Animals; D000918:Antibody Specificity; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000302:isolation & purification / Q000378:metabolism*; D008578:Meninges / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D020033:Protein Isoforms / Q000302:isolation & purification / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017474:Receptors, Laminin / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016207:Cytokines; D007797:Laminin; D020033:Protein Isoforms; D012333:RNA, Messenger; D017474:Receptors, Laminin; D013755:Tetradecanoylphorbol Acetate