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Published online 3 April 2006 doi:10.1084/jem.20051342
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 1007-1019
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ARTICLE

 Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis

Smriti Agrawal1, Per Anderson2, Madeleine Durbeej3, Nico van Rooijen4, Fredrik Ivars2, Ghislain Opdenakker5, and Lydia M. Sorokin1,6

1 Experimental Pathology, 2 Immunology, and 3 Experimental Medical Science, Lund University, Lund 22185, Sweden
4 Vrije Universiteit, Molecular Cell Biology, 1081 BT Amsterdam, Netherlands
5 Immunobiology, Rega Institute for Medical Research, University of Leuven, B-3000 Leuven, Belgium
6 Institute for Physiological Chemistry and Pathobiochemistry, Münster University, 48149 Münster, Germany

CORRESPONDENCE Lydia M. Sorokin: sorokin{at}uni-muenster.de

The endothelial cell monolayer of cerebral vessels and its basement membrane (BM) are ensheathed by the astrocyte endfeet, the leptomeningeal cells, and their associated parenchymal BM, all of which contribute to establishment of the blood–brain barrier (BBB). As a consequence of this unique structure, leukocyte penetration of cerebral vessels is a multistep event. In mouse experimental autoimmune encephalomyelitis (EAE), a widely used central nervous system inflammatory model, leukocytes first penetrate the endothelial cell monolayer and underlying BM using integrin ß1-mediated processes, but mechanisms used to penetrate the second barrier defined by the parenchymal BM and glia limitans remain uninvestigated. We show here that macrophage-derived gelatinase (matrix metalloproteinase [MMP]-2 and MMP-9) activity is crucial for leukocyte penetration of the parenchymal BM. Dystroglycan, a transmembrane receptor that anchors astrocyte endfeet to the parenchymal BM via high affinity interactions with laminins 1 and 2, perlecan and agrin, is identified as a specific substrate of MMP-2 and MMP-9. Ablation of both MMP-2 and MMP-9 in double knockout mice confers resistance to EAE by inhibiting dystroglycan cleavage and preventing leukocyte infiltration. This is the first description of selective in situ proteolytic damage of a BBB-specific molecule at sites of leukocyte infiltration.

Abbreviations used: BBB, blood–brain barrier; BM, basement membrane; CNS, central nervous system; DKO, double KO; EAE, experimental autoimmune encephalomyelitis; GFAP, glial fibrillary acidic protein; MMP, matrix metalloproteinase; MOG, myelin/oligodendrocyte glycoprotein; WGA, wheat germ agglutinin.


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