Abstract 16928: Critical Role of Endoplasmic Reticulum Stress-Regulated CXCL10/CXCR3 Axis in the Ischemia-Reperfusion Injured Tissue
Ischemic stroke is caused by neurologic dysfunction in the brain, spinal cord and retina by blocking blood flow. Mechanisms of neuronal injury caused by ischemia-reperfusion (IR) remain to be defined. Studies in animal models and tissues from patients with IR show the common features of inflammation such as increases in the levels of inflammatory cytokines, chemokines, leukostasis, and leukocyte infiltration.CXCL10 is a chemokine which induces recruitment and activation of inflammatory cells after binding to its receptor CXCR3. Here we hypothesized that the CXCL10/CXCR3 axis has a role in neuronal injury during IR using retina as a model system. Retinal IR was induced by increasing the intraocular pressure up to 110 mm Hg for 45 mins to block the retinal blood flow. The contralateral eye treated was sham control. Expression of CXCL10 mRNA was dramatically increased after IR with a peak expression (247.75 fold) at 6 hours following reperfusion.Consistent with the mRNA level, CXCL10 protein expression was elevated by IR (123.3±32.7 pg/mg protein) compared to sham treatment (20.39±1.18 pg/mg protein). Blockade of the CXC10/CXCR3 axis be deleting CXCR3 gene significantly attenuated IR-induced production of inflammatory molecules (interleukin 1 beta and E-selectin), inhibited recruitment of microglia/monocyte to the superficial retina, reduced peroxynitrite formation, and prevented loss of retinal ganglion cells. In contrast, in a series of in vitro studies, where mouse primary retinal ganglion cells were treated with various doses of CXCL10 (1, 10 and 100ng/ml), a dose dependent cell death response was observed (19.38±0.97%, 23.74±1.11% and 26.15±0.83 respectively). Additionally, IR-induced CXCL10 upregulation was associated with increases in endoplasmic reticulum (ER) stress genes, such as GRP78, ATF4 and CHOP. Inhibition of ER stress with the chemical chaperone 4-phenylbutyric acid and tauroursodeoxycholic acid blocked IR-induced CXCL10 expression by 50% and 30% respectively. These results indicate that ER stress-induced activation of the CXCL10/CXCR3 axis has an essential role in IR-induced retinal neuronal injury.
- © 2013 by American Heart Association, Inc.