title: Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ha
authors.affiliation: Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.|Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.|College of Allied Health Sciences, Georgia Regents University, Augusta, GA, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Narayanan
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lemtalsi
authors.affiliation: Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Smith
authors.affiliation: Department of pharmacology and Toxicology, Georgia Regents University, Augusta, GA, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Caldwell
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.|College of Allied Health Sciences, Georgia Regents University, Augusta, GA, USA.|VA Medical Center, Augusta, GA, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Caldwell
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX, USA.|Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, TX, USA.|Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005901:Glaucoma / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007511:Ischemia / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3