Cargando…

Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma

Acute glaucoma is a leading cause of irreversible blindness in East Asia. The mechanisms underlying retinal neuronal injury induced by a sudden rise in intraocular pressure (IOP) remain obscure. Here we demonstrate that the activation of CXCL10/CXCR3 axis, which mediates the recruitment and activati...

Descripción completa

Detalles Bibliográficos
Autores principales: Ha, Y, Liu, H, Xu, Z, Yokota, H, Narayanan, S P, Lemtalsi, T, Smith, S B, Caldwell, R W, Caldwell, R B, Zhang, W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632306/
https://www.ncbi.nlm.nih.gov/pubmed/26448323
http://dx.doi.org/10.1038/cddis.2015.281
_version_ 1782398999672651776
author Ha, Y
Liu, H
Xu, Z
Yokota, H
Narayanan, S P
Lemtalsi, T
Smith, S B
Caldwell, R W
Caldwell, R B
Zhang, W
author_facet Ha, Y
Liu, H
Xu, Z
Yokota, H
Narayanan, S P
Lemtalsi, T
Smith, S B
Caldwell, R W
Caldwell, R B
Zhang, W
author_sort Ha, Y
collection PubMed
description Acute glaucoma is a leading cause of irreversible blindness in East Asia. The mechanisms underlying retinal neuronal injury induced by a sudden rise in intraocular pressure (IOP) remain obscure. Here we demonstrate that the activation of CXCL10/CXCR3 axis, which mediates the recruitment and activation of inflammatory cells, has a critical role in a mouse model of acute glaucoma. The mRNA and protein expression levels of CXCL10 and CXCR3 were significantly increased after IOP-induced retinal ischemia. Blockade of the CXCR3 pathway by deleting CXCR3 gene significantly attenuated ischemic injury-induced upregulation of inflammatory molecules (interleukin-1β and E-selectin), inhibited the recruitment of microglia/monocyte to the superficial retina, reduced peroxynitrite formation, and prevented the loss of neurons within the ganglion cell layer. In contrast, intravitreal delivery of CXCL10 increased leukocyte recruitment and retinal cell apoptosis. Inhibition of endoplasmic reticulum (ER) stress with chemical chaperones partially blocked ischemic injury-induced CXCL10 upregulation, whereas induction of ER stress with tunicamycin enhanced CXCL10 expression in retina and primary retinal ganglion cells. Interestingly, deleting CXCR3 attenuated ER stress-induced retinal cell death. In conclusion, these results indicate that ER stress-medicated activation of CXCL10/CXCR3 pathway has an important role in retinal inflammation and neuronal injury after high IOP-induced ischemia.
format Online
Article
Text
id pubmed-4632306
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-46323062015-11-16 Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma Ha, Y Liu, H Xu, Z Yokota, H Narayanan, S P Lemtalsi, T Smith, S B Caldwell, R W Caldwell, R B Zhang, W Cell Death Dis Original Article Acute glaucoma is a leading cause of irreversible blindness in East Asia. The mechanisms underlying retinal neuronal injury induced by a sudden rise in intraocular pressure (IOP) remain obscure. Here we demonstrate that the activation of CXCL10/CXCR3 axis, which mediates the recruitment and activation of inflammatory cells, has a critical role in a mouse model of acute glaucoma. The mRNA and protein expression levels of CXCL10 and CXCR3 were significantly increased after IOP-induced retinal ischemia. Blockade of the CXCR3 pathway by deleting CXCR3 gene significantly attenuated ischemic injury-induced upregulation of inflammatory molecules (interleukin-1β and E-selectin), inhibited the recruitment of microglia/monocyte to the superficial retina, reduced peroxynitrite formation, and prevented the loss of neurons within the ganglion cell layer. In contrast, intravitreal delivery of CXCL10 increased leukocyte recruitment and retinal cell apoptosis. Inhibition of endoplasmic reticulum (ER) stress with chemical chaperones partially blocked ischemic injury-induced CXCL10 upregulation, whereas induction of ER stress with tunicamycin enhanced CXCL10 expression in retina and primary retinal ganglion cells. Interestingly, deleting CXCR3 attenuated ER stress-induced retinal cell death. In conclusion, these results indicate that ER stress-medicated activation of CXCL10/CXCR3 pathway has an important role in retinal inflammation and neuronal injury after high IOP-induced ischemia. Nature Publishing Group 2015-10 2015-10-08 /pmc/articles/PMC4632306/ /pubmed/26448323 http://dx.doi.org/10.1038/cddis.2015.281 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Ha, Y
Liu, H
Xu, Z
Yokota, H
Narayanan, S P
Lemtalsi, T
Smith, S B
Caldwell, R W
Caldwell, R B
Zhang, W
Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma
title Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma
title_full Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma
title_fullStr Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma
title_full_unstemmed Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma
title_short Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma
title_sort endoplasmic reticulum stress-regulated cxcr3 pathway mediates inflammation and neuronal injury in acute glaucoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632306/
https://www.ncbi.nlm.nih.gov/pubmed/26448323
http://dx.doi.org/10.1038/cddis.2015.281
work_keys_str_mv AT hay endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT liuh endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT xuz endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT yokotah endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT narayanansp endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT lemtalsit endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT smithsb endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT caldwellrw endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT caldwellrb endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma
AT zhangw endoplasmicreticulumstressregulatedcxcr3pathwaymediatesinflammationandneuronalinjuryinacuteglaucoma