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The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention

Extracellular proteases such as plasminogen activators (PAs) and matrix metalloproteinases modulate cell-cell and cell-matrix interactions. Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic...

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Published in:Journal of neuroinflammation 2013-10, Vol.10 (1), p.124-124, Article 891
Main Authors: Gur-Wahnon, Devorah, Mizrachi, Tehila, Maaravi-Pinto, Florence-Yehudith, Lourbopoulos, Athanasis, Grigoriadis, Nikolaos, Higazi, Abd-Al Roof, Brenner, Talma
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container_title Journal of neuroinflammation
container_volume 10
creator Gur-Wahnon, Devorah
Mizrachi, Tehila
Maaravi-Pinto, Florence-Yehudith
Lourbopoulos, Athanasis
Grigoriadis, Nikolaos
Higazi, Abd-Al Roof
Brenner, Talma
description Extracellular proteases such as plasminogen activators (PAs) and matrix metalloproteinases modulate cell-cell and cell-matrix interactions. Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic disorders such as epilepsy, stroke, brain trauma, Alzheimer's' disease and multiple sclerosis (MS). In the present study, we evaluated the involvement of the PA system in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced by myelin oligodendrocyte glycoprotein (MOG) in mice deficient for the urokinase PA (uPA-/-), or the urokinase PA receptor (uPAR-/-). Mice were evaluated for EAE clinical signs and histopathologic parameters, and compared with wild-type (WT) EAE mice. Lymphocytes from the knockout (KO) and WT mice were analyzed for ex vivo restimulation, cytokine secretion, and antigen presentation. Finally, WT EAE mice were treated with PAI-1dp, an 18 amino acid peptide derived from the PA inhibitor protein (PAI-1). EAE was aggravated in uPA-/- and uPAR-/- mice, and this was accompanied by more severe histopathologic features and microglial activation. By contrast, specific T- cell reactivity towards the encephalitogenic antigen MOG was markedly reduced in the KO animals, as shown by a marked reduction in proliferation and pro-inflammatory cytokine secretion in these mice. Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox. When the mice were treated with PAI-1, a peptide derived from the PA system, a marked and significant improvement in EAE was seen. The clinical improvement was linked to reduced T-cell reactivity, further emphasizing the importance of the PA system in immunomodulation during neuroinflammation. Cumulatively, our results suggest a role for uPA and uPAR in EAE pathogenesis, as exacerbation of disease was seen in their absence. Furthermore, the successful amelioration of EAE by PAI-1 treatment suggests that the PA system can be considered a potential site for therapeutic intervention in the treatment of neuroimmune diseases.
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Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic disorders such as epilepsy, stroke, brain trauma, Alzheimer's' disease and multiple sclerosis (MS). In the present study, we evaluated the involvement of the PA system in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced by myelin oligodendrocyte glycoprotein (MOG) in mice deficient for the urokinase PA (uPA-/-), or the urokinase PA receptor (uPAR-/-). Mice were evaluated for EAE clinical signs and histopathologic parameters, and compared with wild-type (WT) EAE mice. Lymphocytes from the knockout (KO) and WT mice were analyzed for ex vivo restimulation, cytokine secretion, and antigen presentation. Finally, WT EAE mice were treated with PAI-1dp, an 18 amino acid peptide derived from the PA inhibitor protein (PAI-1). EAE was aggravated in uPA-/- and uPAR-/- mice, and this was accompanied by more severe histopathologic features and microglial activation. By contrast, specific T- cell reactivity towards the encephalitogenic antigen MOG was markedly reduced in the KO animals, as shown by a marked reduction in proliferation and pro-inflammatory cytokine secretion in these mice. Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox. When the mice were treated with PAI-1, a peptide derived from the PA system, a marked and significant improvement in EAE was seen. The clinical improvement was linked to reduced T-cell reactivity, further emphasizing the importance of the PA system in immunomodulation during neuroinflammation. Cumulatively, our results suggest a role for uPA and uPAR in EAE pathogenesis, as exacerbation of disease was seen in their absence. 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This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2013 Gur-Wahnon et al.; licensee BioMed Central Ltd. 2013 Gur-Wahnon et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-b537t-c85fb512e0ad2bc5c05db9310af3a6a367ed6763b6d674b33b14ccc278f11a63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852474/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1442898638?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24120085$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gur-Wahnon, Devorah</creatorcontrib><creatorcontrib>Mizrachi, Tehila</creatorcontrib><creatorcontrib>Maaravi-Pinto, Florence-Yehudith</creatorcontrib><creatorcontrib>Lourbopoulos, Athanasis</creatorcontrib><creatorcontrib>Grigoriadis, Nikolaos</creatorcontrib><creatorcontrib>Higazi, Abd-Al Roof</creatorcontrib><creatorcontrib>Brenner, Talma</creatorcontrib><title>The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention</title><title>Journal of neuroinflammation</title><addtitle>J Neuroinflammation</addtitle><description>Extracellular proteases such as plasminogen activators (PAs) and matrix metalloproteinases modulate cell-cell and cell-matrix interactions. Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic disorders such as epilepsy, stroke, brain trauma, Alzheimer's' disease and multiple sclerosis (MS). In the present study, we evaluated the involvement of the PA system in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced by myelin oligodendrocyte glycoprotein (MOG) in mice deficient for the urokinase PA (uPA-/-), or the urokinase PA receptor (uPAR-/-). Mice were evaluated for EAE clinical signs and histopathologic parameters, and compared with wild-type (WT) EAE mice. Lymphocytes from the knockout (KO) and WT mice were analyzed for ex vivo restimulation, cytokine secretion, and antigen presentation. Finally, WT EAE mice were treated with PAI-1dp, an 18 amino acid peptide derived from the PA inhibitor protein (PAI-1). 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subjects Alzheimer's disease
Analysis
Animals
Antigens
Apoptosis
Blood-brain barrier
Brain research
Cell adhesion & migration
Cell culture
Central Nervous System - immunology
Central Nervous System - metabolism
Central Nervous System - pathology
Disease
Encephalomyelitis
Encephalomyelitis, Autoimmune, Experimental - immunology
Encephalomyelitis, Autoimmune, Experimental - metabolism
Encephalomyelitis, Autoimmune, Experimental - pathology
Enzymes
Female
Inflammation
Inflammation - immunology
Inflammation - metabolism
Inflammation - pathology
Laboratory animals
Mediation
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiple sclerosis
Peptides
Physiological aspects
Plasminogen Activators - immunology
Plasminogen Activators - metabolism
Receptors, Urokinase Plasminogen Activator - immunology
Receptors, Urokinase Plasminogen Activator - metabolism
Rodents
Studies
T cells
Thrombolytic drugs
title The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention
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