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

2006 ◽  
Vol 173 (2) ◽  
pp. i2-i2 ◽  
Author(s):  
Smriti Agrawal ◽  
Per Anderson ◽  
Madeleine Durbeej ◽  
Nico van Rooijen ◽  
Fredrik Ivars ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Leukocyte Extravasation ◽  
Experimental Autoimmune

scholarly journals Inhibitory Effect of Matrine on Blood-Brain Barrier Disruption for the Treatment of Experimental Autoimmune Encephalomyelitis

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Su Zhang ◽  
Quan-Cheng Kan ◽  
Yuming Xu ◽  
Guang-Xian Zhang ◽  
Lin Zhu
Keyword(s):  
Basement Membrane ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Blood Brain Barrier ◽  
Adaptor Protein ◽  
Brain Barrier ◽  
Autoimmune Encephalomyelitis ◽  
Novel Therapy ◽  
Cns Inflammation ◽  
Blood Brain ◽  
Experimental Autoimmune

Dysfunction of the blood-brain barrier (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a therapeutic effect comparable to dexamethasone (DEX) in EAE rats, with reduced Evans Blue extravasation, increased expression of collagen IV, the major component of the basement membrane, and the structure of tight junction (TJ) adaptor protein Zonula occludens-1 (ZO-1). Furthermore, MAT treatment attenuated expression of matrix metalloproteinase-9 and -2 (MMP-9/-2), while it increased the expression of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1/-2). Our findings demonstrate that MAT reduces BBB leakage by strengthening basement membrane, inhibiting activities of MMP-2 and -9, and upregulating their inhibitors. Taken together, our results identify a novel mechanism underlying the effect of MAT, a natural compound that could be a novel therapy for MS.

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

2006 ◽  
Vol 203 (4) ◽  
pp. 1007-1019 ◽  
Author(s):  
Smriti Agrawal ◽  
Per Anderson ◽  
Madeleine Durbeej ◽  
Nico van Rooijen ◽  
Fredrik Ivars ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Basement Membrane ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cell Monolayer ◽  
Cerebral Vessels ◽  
Leukocyte Infiltration ◽  
Endothelial Cell Monolayer ◽  
Autoimmune Encephalomyelitis ◽  
Astrocyte Endfeet ◽  
Experimental Autoimmune

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 β1-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.

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