Endothelial Cell Laminin Isoforms, Laminins 8 and 10, Play Decisive Roles in T Cell Recruitment Across the Blood-Brain Barrier in Experimental Autoimmune Encephalomyelitis

doi:10.1083/jcb.153.5.933

Published online 21 May 2001. doi:10.1083/jcb.153.5.933

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© The Rockefeller University Press, 0021-9525/2001/5/933/ $5.00
The Journal of Cell Biology, Volume 153, Number 5, May 28, 2001 933-946

Original Article

Endothelial Cell Laminin Isoforms, Laminins 8 and 10, Play Decisive Roles in T Cell Recruitment Across the Blood–Brain Barrier in Experimental Autoimmune Encephalomyelitis

Michael Sixt^a, Britta Engelhardt^c, Friederike Pausch^a, Rupert Hallmann^b, Olaf Wendler^a, and Lydia M. Sorokin^a
^a Interdisciplinary Center for Clinical Research (IZKF), Nikolaus Fiebiger Center, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
^b Department of Experimental Medicine I, Nikolaus Fiebiger Center, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
^c Max-Planck Institute for Physiological and Clinical Research, W.G. Kerckhoff-Institute, Department of Vascular Cell Biology, 61231 Bad Nauheim, Germany

Correspondence to: Lydia M. Sorokin, Interdisciplinary Center for Clinical Research (IZKF), Nikolaus Fiebiger Center for Molecular Medicine, Glückstr. 6, 91054 Erlangen, Germany. Tel:(49) 9131-853-9301 Fax:(49) 9131-853-9311 E-mail:lsorokin{at}molmed.uni-erlangen.de.

An active involvement of blood–brain barrier endothelialcell basement membranes in development of inflammatory lesionsin the central nervous system (CNS) has not been consideredto date. Here we investigated the molecular composition andpossible function of the extracellular matrix encountered byextravasating T lymphocytes during experimental autoimmune encephalomyelitis(EAE).

Endothelial basement membranes contained laminin 8 ( ${alpha}$ 4ß1 ${gamma}$ 1)and/or 10 ( ${alpha}$ 5ß1 ${gamma}$ 1) and their expression was influencedby proinflammatory cytokines or angiostatic agents. T cellsemigrating into the CNS during EAE encountered two biochemicallydistinct basement membranes, the endothelial (containing laminins8 and 10) and the parenchymal (containing laminins 1 and 2)basement membranes. However, inflammatory cuffs occurred exclusivelyaround 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 revealedadhesion to laminins 8 and 10, whereas binding to laminins 1and 2 could not be induced. Downregulation of integrin ${alpha}$ 6 oncerebral endothelium at sites of T cell infiltration, plus ahigh turnover of laminin 8 at these sites, suggested two possibleroles for laminin 8 in the endothelial basement membrane: oneat the level of the endothelial cells resulting in reduced adhesionand, thereby, increased penetrability of the monolayer; andsecondly at the level of the T cells providing direct signalsto the transmigrating cells.

Key Words: laminin, experimental autoimmune encephalomyelitis, endothelium,basement membranes, inflammation

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