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.
Highlights
Western countries, it is less common, but it still has much higher rate to induce vision impairment and blindness than open-angle glaucoma.[2]
To investigate whether CXCR3 signaling is implicated in acute glaucoma, we examined the expression of CXCR3 and its ligands in a mouse model of acute glaucoma, in which retinal ischemia is induced by acute elevation of intraocular pressure (IOP).[4]
Using a mouse model of acute glaucoma, we found that IOP-induced retinal ischemic injury increases the expression of CXCR3 as well as its two ligands CXCL10 and CXCL4 in retina
Summary
It is less common, but it still has much higher rate to induce vision impairment and blindness than open-angle glaucoma.[2]. T cells and microglia/macrophage.[10,14,15,16,17] CXCL10 expression is increased in the central nervous system in neurodegenerative diseases including Alzheimer’s disease and multiple sclerosis.[18,19,20,21] The activation of CXCL10/CXCR3 axis has been shown to promote microglia recruitment and induce neuronal cell death in several models of neurodegeneration.[22,23] The role of CXCL10/CXCR3 pathway in glaucomatous optic neuropathy is unknown. The upregulation of CXCL10 and CXCR3 expression in retina is at least partially mediated by endoplasmic reticulum (ER) stress after ischemia
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