RRC ID 1856
Author Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM.
Title Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis.
Journal J. Exp. Med.
Abstract 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 beta1-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.
Volume 203(4)
Pages 1007-19
Published 2006-4-17
DOI 10.1084/jem.20051342
PII jem.20051342
PMID 16585265
PMC PMC2118280
MeSH Animals Astrocytes / metabolism Basement Membrane / enzymology Basement Membrane / metabolism* Cells, Cultured Dystroglycans / metabolism* Encephalomyelitis, Autoimmune, Experimental / enzymology Encephalomyelitis, Autoimmune, Experimental / metabolism* Gelatinases / genetics Gelatinases / metabolism Hydrolysis Leukocyte Rolling / immunology* Leukocytes / cytology Leukocytes / enzymology Macrophages / enzymology Matrix Metalloproteinase 2 / genetics Matrix Metalloproteinase 2 / metabolism Matrix Metalloproteinase 9 / genetics Matrix Metalloproteinase 9 / metabolism Mice Mice, Inbred C57BL Mice, Knockout
IF 10.892
Times Cited 273
Mice GelA KO