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Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo

BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS). It is widely accepted that inflammatory cells play major roles in the pathogenesis of MS, possibly through the use of serine protease granzyme B (GrB) secreted from th...

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Autores principales: Haile, Yohannes, Carmine-Simmen, Katia, Olechowski, Camille, Kerr, Bradley, Bleackley, R. Chris, Giuliani, Fabrizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558826/
https://www.ncbi.nlm.nih.gov/pubmed/26337722
http://dx.doi.org/10.1186/s12974-015-0376-7
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author Haile, Yohannes
Carmine-Simmen, Katia
Olechowski, Camille
Kerr, Bradley
Bleackley, R. Chris
Giuliani, Fabrizio
author_facet Haile, Yohannes
Carmine-Simmen, Katia
Olechowski, Camille
Kerr, Bradley
Bleackley, R. Chris
Giuliani, Fabrizio
author_sort Haile, Yohannes
collection PubMed
description BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS). It is widely accepted that inflammatory cells play major roles in the pathogenesis of MS, possibly through the use of serine protease granzyme B (GrB) secreted from the granules of cytotoxic T cells. We have previously identified GrB as a mediator of axonal injury and neuronal death. In this study, our goal was to evaluate the effect of GrB inhibition in the human system in vitro, and in vivo in EAE using the newly isolated GrB-inhibitor serpina3n. METHODS: We used a well-established in vitro model of neuroinflammation characterized by a co-culture system between human fetal neurons and lymphocytes. In vivo, we induced EAE in 10- to 12-week-old female C57/BL6 mice and treated them intravenously with serpina3n. RESULTS: In the in vitro co-culture system, pre-treatment of lymphocytes with serpina3n prevented neuronal killing and cleavage of the cytoskeletal protein alpha-tubulin, a known substrate for GrB. Moreover, in EAE, 50 μg serpina3n substantially reduced the severity of the disease. This dose was administered intravenously twice at days 7 and 20 post EAE induction. serpina3n treatment reduced axonal and neuronal injury compared to the vehicle-treated control group and maintained the integrity of myelin. Interestingly, serpina3n treatment did not seem to reduce the infiltration of immune cells (CD4(+) and CD8(+) T cells) into the CNS. CONCLUSION: Our data suggest further studies on serpina3n as a potentially novel therapeutic strategy for the treatment of inflammatory-mediated neurodegenerative diseases such as MS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0376-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-45588262015-09-04 Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo Haile, Yohannes Carmine-Simmen, Katia Olechowski, Camille Kerr, Bradley Bleackley, R. Chris Giuliani, Fabrizio J Neuroinflammation Research BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS). It is widely accepted that inflammatory cells play major roles in the pathogenesis of MS, possibly through the use of serine protease granzyme B (GrB) secreted from the granules of cytotoxic T cells. We have previously identified GrB as a mediator of axonal injury and neuronal death. In this study, our goal was to evaluate the effect of GrB inhibition in the human system in vitro, and in vivo in EAE using the newly isolated GrB-inhibitor serpina3n. METHODS: We used a well-established in vitro model of neuroinflammation characterized by a co-culture system between human fetal neurons and lymphocytes. In vivo, we induced EAE in 10- to 12-week-old female C57/BL6 mice and treated them intravenously with serpina3n. RESULTS: In the in vitro co-culture system, pre-treatment of lymphocytes with serpina3n prevented neuronal killing and cleavage of the cytoskeletal protein alpha-tubulin, a known substrate for GrB. Moreover, in EAE, 50 μg serpina3n substantially reduced the severity of the disease. This dose was administered intravenously twice at days 7 and 20 post EAE induction. serpina3n treatment reduced axonal and neuronal injury compared to the vehicle-treated control group and maintained the integrity of myelin. Interestingly, serpina3n treatment did not seem to reduce the infiltration of immune cells (CD4(+) and CD8(+) T cells) into the CNS. CONCLUSION: Our data suggest further studies on serpina3n as a potentially novel therapeutic strategy for the treatment of inflammatory-mediated neurodegenerative diseases such as MS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0376-7) contains supplementary material, which is available to authorized users. BioMed Central 2015-09-04 /pmc/articles/PMC4558826/ /pubmed/26337722 http://dx.doi.org/10.1186/s12974-015-0376-7 Text en © Haile et al. 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Haile, Yohannes
Carmine-Simmen, Katia
Olechowski, Camille
Kerr, Bradley
Bleackley, R. Chris
Giuliani, Fabrizio
Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
title Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
title_full Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
title_fullStr Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
title_full_unstemmed Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
title_short Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
title_sort granzyme b-inhibitor serpina3n induces neuroprotection in vitro and in vivo
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558826/
https://www.ncbi.nlm.nih.gov/pubmed/26337722
http://dx.doi.org/10.1186/s12974-015-0376-7
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