Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. 1658 65

Available treatments for multiple sclerosis (MS) require frequent injections and have significant side effects. Proteases generated during inflammation are involved in the induction of tissue damage during inflammatory demyelination in the central nervous system (CNS). The Bowman-Birk Inhibitor (BBI), a soy-derived protease inhibitor with anti-carcinogenic and anti-inflammatory properties, has been shown to be well tolerated in clinical trials for pre-cancerous conditions, such as oral leukoplakia and the inflammatory disease, ulcerative colitis. We hypothesized that BBI may modulate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The BBI concentrate (BBIC), a soybean extract enriched in BBI, was administered to myelin basic protein (MBP)-immunized Lewis rats by gastric gavage in different treatment regimens, during the induction or the effector phase of disease. BBIC significantly delayed disease onset and suppressed disease severity, clinically and pathologically, in all treatment protocols. Both in vitro and ex vivo, BBIC inhibited MBP-specific proliferation of lymph node cells. BBIC reduced the activity of matrix metalloproteinase (MMP)-2 and -9 in spleen cell supernatants and was detected in the CNS of treated rats. BBIC suppresses EAE, it can be administered orally, and it is safe and relatively inexpensive. It may have a therapeutic role in patients with MS.
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PMID:The protease inhibitor, Bowman-Birk Inhibitor, suppresses experimental autoimmune encephalomyelitis: a potential oral therapy for multiple sclerosis. 1726 95

The matrix metalloproteinases (MMPs) are implicated in the pathology of multiple sclerosis (MS). This review summarizes the consequences of upregulation of MMP members in MS as well as in an animal model of the disease, experimental autoimmune encephalomyelitis (EAE). The pathogenic roles of MMPs are considered, especially in the transmigration of leukocytes into the CNS. We review the evidence that interferon-beta, an immunomodulator that is commonly used in MS, affects MMP expression in the disease. The potential of minocycline as a therapy in MS, based on its activity as an MMP inhibitor, is discussed. Besides affecting MMPs, minocycline may have other actions that help account for its possible utility in MS.
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PMID:Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. 1738 65

Early in the pathogenesis of multiple sclerosis, the blood-brain barrier is compromised, which leads to deposition of the plasma proteins fibronectin and vitronectin in cerebral parenchyma. In light of our previous finding that microglial activation in vitro is strongly promoted by fibronectin and vitronectin, we set out to examine the possibility that modulation of microglial activation by fibronectin or vitronectin is an important regulatory mechanism in vivo. In an experimental autoimmune encephalomyelitis mouse model of demyelination, total brain levels of fibronectin and vitronectin were strongly increased and there was a close relationship between fibronectin and vitronectin deposition, microglial activation, and microglial expression of matrix metalloproteinase-9. In murine cell culture, flow cytometry for MHC class I and gelatin zymography revealed that microglial activation and expression of pro-matrix metalloproteinase-9 were significantly increased by fibronectin and vitronectin. Function-blocking studies showed that the influence of fibronectin and vitronectin was mediated by the alpha(5)beta(1) and alpha(v)beta(5) integrins, respectively. Taken together, this work suggests that fibronectin and vitronectin deposition during demyelinating disease is an important influence on microglial activation state. Furthermore, it provides the first evidence that the alpha(5)beta(1) and alpha(v)beta(5) integrins are important mediators of microglial activation.
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PMID:Fibronectin- and vitronectin-induced microglial activation and matrix metalloproteinase-9 expression is mediated by integrins alpha5beta1 and alphavbeta5. 1754 54

FTY720 (fingolimod) is an oral sphingosine-1 phosphate (S1P) receptor modulator in phase III development for the treatment of multiple sclerosis. To further investigate its mode of action, we analyzed gene expression in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). FTY720 downregulated inflammatory genes in addition to vascular adhesion molecules. It decreased the matrix metalloproteinase gene MMP-9 and increased its counterregulator--tissue inhibitor of metalloproteinase, TIMP-1--resulting in a proteolytic balance that favors preservation of blood-brain-barrier (BBB) integrity. Furthermore, FTY720 reduced S1P lyase that increases the S1P concentration in the brain, in line with a marked reversal of neurological deficits and raising the possibility for enhanced triggering of S1P receptors on resident brain cells. This is accompanied by an increase in S1P(1) and S1P(5) in contrast with the attenuation of S1P(3) and S1P(4). Late-stage rescue therapy with FTY720, even up to 1 month after EAE onset, reversed BBB leakiness and reduced demyelination, along with normalization of neurologic function. Our results indicate rapid blockade of ongoing disease processes by FTY720, and structural restoration of the CNS parenchyma, which is likely caused by the inhibition of autoimmune T cell infiltration and direct modulation of microvascular and/or glial cells.
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PMID:FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. 1854 Sep 45

Several matrix metalloproteinase (MMP) members contribute to pathology in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). As the role of MMP-12 in EAE has been understudied, we examined its expression in EAE and in vitro. MMP-12 transcripts increased with EAE, and protein was localized to a subset of macrophages/microglia. The temporal expression of MMP-12 largely corresponded to that of cytokines, and we demonstrate that IL-1beta and TNF-alpha promoted MMP-12 expression in cultured macrophages. We postulate that cytokine - MMP-12 interactions are important in the disease process of EAE.
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PMID:Expression and regulation of matrix metalloproteinase-12 in experimental autoimmune encephalomyelitis and by bone marrow derived macrophages in vitro. 1854 53

The BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) induces demyelinating disease in susceptible mice comparable to human multiple sclerosis. Recent in vivo studies showed that matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of MMPs, TIMPs) are associated with demyelination in Theiler's murine encephalomyelitis. The present study was performed to evaluate the in vitro MMP and TIMP expression in astrocytes and microglia following TMEV infection. Brain cell cultures from SJL/J mice were infected with the BeAn strain of TMEV and the expressions of 11 MMPs and 4 TIMPs were evaluated by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) at different time points post infection (p.i.). In control astrocytes and microglia, a constitutive expression of MMP-2, -3, -9, -10, -12, -13, -14, -15, -24 and TIMP-2 to -4 was detected. In addition, TIMP-1 and MMP-11 was found in astrocytes only, and MMP-7 was absent in both cells cultures. RT-qPCR demonstrated high virus RNA copy numbers in astrocytes and a low amount in microglia. In accordance, TMEV antigen was detected in astrocytes, whereas it was below the limit of detection in microglia. MMP-3, -9, -10, -12, and -13 as well as TIMP-1 were the enzymes most prominently up-regulated in TMEV-infected astrocytes. In contrast, TMEV infection was associated with a down-regulation of MMPs and TIMPs in microglia. Conclusively, in addition to inflammatory infiltrates, TMEV-induced astrocytic MMPs might trigger a proteolysis cascade leading to an opening of the blood-brain barrier and demyelination in vivo.
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PMID:Differential transcription of matrix-metalloproteinase genes in primary mouse astrocytes and microglia infected with Theiler's murine encephalomyelitis virus. 1856 55

The aim of this study was to establish an animal model of experimental allergic encephalomyelitis (EAE) and examine the basic pathological changes, as well as expression and distribution of MMP-2 and MMP-9, in Wistar rats. Tissue sections were processed for HE staining, Weil myelin staining, and modified Bielschowsky staining. Expression and distribution of glial fibrillary acidic protein (GFAP), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) were detected with immunohistochemistry. We divided the EAE into five types, depending on pathological characteristics and clinical manifestations: acute EAE, relapsing-remitting EAE, progressive EAE, benign EAE, and asymptomatic EAE. Rats with acute EAE suffered from quick, severe attacks with widespread inflammatory cells and axonal loss. No demyelination or astrocytic hyperplasia was found around the lesions. Rats with relapsing-remitting EAE broke down twice, with many perivascular cuffs and demyelinating plaques in lesions; hyperplastic and hypertrophic astrocytes characterized old lesions and axonal loss was evident. Rats suffering from progressive EAE exhibited continuous aggravation without improvement, accompanied by perivascular cuffs, demyelination, increased gliocytes and axonal damage. Rats with benign EAE recovered to a normal state with obviously decreased inflammatory cells and almost entirely unaffected myelin and axons. Rats with asymptomatic EAE also had various pathological changes that were not coincident with their clinical manifestations. Elevated expression of MMP-2 and MMP-9 was concordant in different types of EAE, but the extent differed in each type of EAE. MMP-2 and MMP-9 can be expressed in the form of vascular endothelial cells, meninges, or accumulated inflammatory cells. Multiple clinical courses of disease were demonstrated in Wistar rat EAE, with attributes similar to multiple sclerosis (MS) in clinical and pathological characteristics. Elevated expression of MMP-2 and MMP-9 may play a role in some aspects of pathological changes in EAE, for example, destroying the blood-brain barrier, degrading the myelin sheath, and damaging axons.
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PMID:Pathological findings in rats with experimental allergic encephalomyelitis. 1913 94

The elevation of several members of the matrix metalloproteinase (MMP) family promotes the pathophysiology of both multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Nonetheless, given the multiple activities of MMPs, it remains possible that increased levels of a particular MMP may have beneficial functions during disease progression. We reported previously that MMP-12(-/-) mice of the 129/SvEv strain had a poorer EAE outcome than wild-type controls. However, we did not determine further differences in disease profiles between these groups. Using the EAE model in 129/SvEv mice, we report that disease in both wild-type and MMP-12(-/-) mice follows a relapsing-remitting course. Although both mouse groups had similar clinical onsets, subsequent relapses were more severe in MMP-12(-/-) mice; their residual disability at remission was also higher compared with wild-type controls. The worsened relapses and remissions in MMP-12(-/-) mice occurred despite a deficiency of the antigen recall capacity of lymph node-derived cells as well as a reduction in the proportion of macrophages in the spinal cord during the chronic phase of EAE. Significantly, large increases of levels of chemokines and cytokines were found in the spinal cords of MMP-12(-/-) mice during chronic EAE. These results highlight MMP-12 as a beneficial enzyme in EAE and suggest that therapeutic interventions in multiple sclerosis should avoid targeting MMP-12.
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PMID:Matrix metalloproteinase-12 deficiency worsens relapsing-remitting experimental autoimmune encephalomyelitis in association with cytokine and chemokine dysregulation. 1921 36

The administration of ex vivo culture-expanded mesenchymal stromal cells (MSCs) has been shown to reverse symptomatic neuroinflammation observed in experimental autoimmune encephalomyelitis (EAE). The mechanism by which this therapeutic effect occurs remains unknown. In an effort to decipher MSC mode of action, we found that MSC conditioned medium inhibits EAE-derived CD4 T cell activation by suppressing STAT3 phosphorylation via MSC-derived CCL2. Further analysis demonstrates that the effect is dependent on MSC-driven matrix metalloproteinase proteolytic processing of CCL2 to an antagonistic derivative. We also show that antagonistic CCL2 suppresses phosphorylation of AKT and leads to a reciprocal increased phosphorylation of ERK associated with an up-regulation of B7.H1 in CD4 T cells derived from EAE mice. CD4 T cell infiltration of the spinal cord of MSC-treated group was robustly decreased along with reduced plasma levels of IL-17 and TNF-alpha levels and in vitro from restimulated splenocytes. The key role of MSC-derived CCL2 was confirmed by the observed loss of function of CCL2(-/-) MSCs in EAE mice. In summary, this is the first report of MSCs modulating EAE biology via the paracrine conversion of CCL2 from agonist to antagonist of CD4 Th17 cell function.
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PMID:Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. 1941 50


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