RRC ID |
1856
|
著者 |
Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM.
|
タイトル |
Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis.
|
ジャーナル |
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.
|
巻・号 |
203(4)
|
ページ |
1007-19
|
公開日 |
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 |
11.743
|
引用数 |
353
|
WOS 分野
|
IMMUNOLOGY
MEDICINE, RESEARCH & EXPERIMENTAL
|
リソース情報 |
実験動物マウス |
RBRC00398 |