Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation

Autores
Cueva Vargas, Jorge L.; Osswald, Ingrid K.; Unsain, Nicolas; Aurousseau, Mark R.; Barker, Philip A.; Bowie, Derek; Di Polo, Adriana
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs). Tumor necrosis factorα (TNFα) signaling has been linked to RGC damage, however, the mechanism by which TNFα promotes neuronal death remains poorly defined. Using an in vivo rat glaucoma model, we show that TNFα is upregulated by Müller cells and microglia/macrophages soon after induction of ocular hypertension. Administration of XPro1595, a selective inhibitor of soluble TNFα, effectively protects RGC soma and axons. Using cobalt permeability assays, we further demonstrate that endogenous soluble TNFα triggers the upregulation of Ca2+-permeable AMPA receptor (CP-AMPAR) expression in RGCs of glaucomatous eyes. CP-AMPAR activation is not caused by defects in GluA2 subunit mRNA editing, but rather reflects selective downregulation of GluA2 in neurons exposed to elevated eye pressure. Intraocular administration of selective CP-AMPAR blockers promotes robust RGC survival supporting a critical role for non-NMDA glutamate receptors in neuronal death. Our study identifies glia-derived soluble TNFα as a major inducer of RGC death through activation of CP-AMPARs, thereby establishing a novel link between neuroinflammation and cell loss in glaucoma.
Fil: Cueva Vargas, Jorge L.. University of Montreal; Canadá
Fil: Osswald, Ingrid K.. McGill University; Canadá
Fil: Unsain, Nicolas. McGill University. Montreal Neurological Institute and Hospital; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Aurousseau, Mark R.. McGill University; Canadá
Fil: Barker, Philip A.. McGill University. Montreal Neurological Institute and Hospital; Canadá
Fil: Bowie, Derek. McGill University; Canadá
Fil: Di Polo, Adriana. University of Montreal; Canadá
Materia
AMPA RECEPTOR
CALCIUM
GLAUCOMA
NEUROINFLAMMATION
RETINAL GANGLION CELL
TUMOR NECROSIS FACTOR
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/69435
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/69435
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activationCueva Vargas, Jorge L.Osswald, Ingrid K.Unsain, NicolasAurousseau, Mark R.Barker, Philip A.Bowie, DerekDi Polo, AdrianaAMPA RECEPTORCALCIUMGLAUCOMANEUROINFLAMMATIONRETINAL GANGLION CELLTUMOR NECROSIS FACTORhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs). Tumor necrosis factorα (TNFα) signaling has been linked to RGC damage, however, the mechanism by which TNFα promotes neuronal death remains poorly defined. Using an in vivo rat glaucoma model, we show that TNFα is upregulated by Müller cells and microglia/macrophages soon after induction of ocular hypertension. Administration of XPro1595, a selective inhibitor of soluble TNFα, effectively protects RGC soma and axons. Using cobalt permeability assays, we further demonstrate that endogenous soluble TNFα triggers the upregulation of Ca2+-permeable AMPA receptor (CP-AMPAR) expression in RGCs of glaucomatous eyes. CP-AMPAR activation is not caused by defects in GluA2 subunit mRNA editing, but rather reflects selective downregulation of GluA2 in neurons exposed to elevated eye pressure. Intraocular administration of selective CP-AMPAR blockers promotes robust RGC survival supporting a critical role for non-NMDA glutamate receptors in neuronal death. Our study identifies glia-derived soluble TNFα as a major inducer of RGC death through activation of CP-AMPARs, thereby establishing a novel link between neuroinflammation and cell loss in glaucoma.Fil: Cueva Vargas, Jorge L.. University of Montreal; CanadáFil: Osswald, Ingrid K.. McGill University; CanadáFil: Unsain, Nicolas. McGill University. Montreal Neurological Institute and Hospital; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Aurousseau, Mark R.. McGill University; CanadáFil: Barker, Philip A.. McGill University. Montreal Neurological Institute and Hospital; CanadáFil: Bowie, Derek. McGill University; CanadáFil: Di Polo, Adriana. University of Montreal; CanadáSociety for Neuroscience2015-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/69435Cueva Vargas, Jorge L.; Osswald, Ingrid K.; Unsain, Nicolas; Aurousseau, Mark R.; Barker, Philip A.; et al.; Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation; Society for Neuroscience; Journal of Neuroscience; 35; 35; 9-2015; 12088-121020270-6474CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.1273-15.2015info:eu-repo/semantics/altIdentifier/url/http://www.jneurosci.org/content/35/35/12088info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:16:13Zoai:ri.conicet.gov.ar:11336/69435instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:16:13.896CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
title Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
spellingShingle Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
Cueva Vargas, Jorge L.
AMPA RECEPTOR
CALCIUM
GLAUCOMA
NEUROINFLAMMATION
RETINAL GANGLION CELL
TUMOR NECROSIS FACTOR
title_short Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
title_full Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
title_fullStr Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
title_full_unstemmed Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
title_sort Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation
dc.creator.none.fl_str_mv Cueva Vargas, Jorge L.
Osswald, Ingrid K.
Unsain, Nicolas
Aurousseau, Mark R.
Barker, Philip A.
Bowie, Derek
Di Polo, Adriana
author Cueva Vargas, Jorge L.
author_facet Cueva Vargas, Jorge L.
Osswald, Ingrid K.
Unsain, Nicolas
Aurousseau, Mark R.
Barker, Philip A.
Bowie, Derek
Di Polo, Adriana
author_role author
author2 Osswald, Ingrid K.
Unsain, Nicolas
Aurousseau, Mark R.
Barker, Philip A.
Bowie, Derek
Di Polo, Adriana
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv AMPA RECEPTOR
CALCIUM
GLAUCOMA
NEUROINFLAMMATION
RETINAL GANGLION CELL
TUMOR NECROSIS FACTOR
topic AMPA RECEPTOR
CALCIUM
GLAUCOMA
NEUROINFLAMMATION
RETINAL GANGLION CELL
TUMOR NECROSIS FACTOR
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs). Tumor necrosis factorα (TNFα) signaling has been linked to RGC damage, however, the mechanism by which TNFα promotes neuronal death remains poorly defined. Using an in vivo rat glaucoma model, we show that TNFα is upregulated by Müller cells and microglia/macrophages soon after induction of ocular hypertension. Administration of XPro1595, a selective inhibitor of soluble TNFα, effectively protects RGC soma and axons. Using cobalt permeability assays, we further demonstrate that endogenous soluble TNFα triggers the upregulation of Ca2+-permeable AMPA receptor (CP-AMPAR) expression in RGCs of glaucomatous eyes. CP-AMPAR activation is not caused by defects in GluA2 subunit mRNA editing, but rather reflects selective downregulation of GluA2 in neurons exposed to elevated eye pressure. Intraocular administration of selective CP-AMPAR blockers promotes robust RGC survival supporting a critical role for non-NMDA glutamate receptors in neuronal death. Our study identifies glia-derived soluble TNFα as a major inducer of RGC death through activation of CP-AMPARs, thereby establishing a novel link between neuroinflammation and cell loss in glaucoma.
Fil: Cueva Vargas, Jorge L.. University of Montreal; Canadá
Fil: Osswald, Ingrid K.. McGill University; Canadá
Fil: Unsain, Nicolas. McGill University. Montreal Neurological Institute and Hospital; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Aurousseau, Mark R.. McGill University; Canadá
Fil: Barker, Philip A.. McGill University. Montreal Neurological Institute and Hospital; Canadá
Fil: Bowie, Derek. McGill University; Canadá
Fil: Di Polo, Adriana. University of Montreal; Canadá
description Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs). Tumor necrosis factorα (TNFα) signaling has been linked to RGC damage, however, the mechanism by which TNFα promotes neuronal death remains poorly defined. Using an in vivo rat glaucoma model, we show that TNFα is upregulated by Müller cells and microglia/macrophages soon after induction of ocular hypertension. Administration of XPro1595, a selective inhibitor of soluble TNFα, effectively protects RGC soma and axons. Using cobalt permeability assays, we further demonstrate that endogenous soluble TNFα triggers the upregulation of Ca2+-permeable AMPA receptor (CP-AMPAR) expression in RGCs of glaucomatous eyes. CP-AMPAR activation is not caused by defects in GluA2 subunit mRNA editing, but rather reflects selective downregulation of GluA2 in neurons exposed to elevated eye pressure. Intraocular administration of selective CP-AMPAR blockers promotes robust RGC survival supporting a critical role for non-NMDA glutamate receptors in neuronal death. Our study identifies glia-derived soluble TNFα as a major inducer of RGC death through activation of CP-AMPARs, thereby establishing a novel link between neuroinflammation and cell loss in glaucoma.
publishDate 2015
dc.date.none.fl_str_mv 2015-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/69435
Cueva Vargas, Jorge L.; Osswald, Ingrid K.; Unsain, Nicolas; Aurousseau, Mark R.; Barker, Philip A.; et al.; Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation; Society for Neuroscience; Journal of Neuroscience; 35; 35; 9-2015; 12088-12102
0270-6474
CONICET Digital
CONICET
url http://hdl.handle.net/11336/69435
identifier_str_mv Cueva Vargas, Jorge L.; Osswald, Ingrid K.; Unsain, Nicolas; Aurousseau, Mark R.; Barker, Philip A.; et al.; Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable ampa receptor activation; Society for Neuroscience; Journal of Neuroscience; 35; 35; 9-2015; 12088-12102
0270-6474
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.1273-15.2015
info:eu-repo/semantics/altIdentifier/url/http://www.jneurosci.org/content/35/35/12088
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844614105624739840
score 13.070432

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