April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Endoplasmic Reticulum Stress-regulated CXCL10/CXCR3 pathway mediates inflammation and neuronal injury after retinal ischemia
Author Affiliations & Notes
  • Yonju Ha
    Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX
  • Hua Liu
    Center for Biomedical Engineering, University of Texas Medical Branch, Galveston, TX
  • Zhimin Xu
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Harumasa Yokota
    Ophthalmology, Asahikawa Medical University, Asahikawa, Japan
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Tahira Lemtalsi
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Sylvia B Smith
    Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA
  • Robert William Caldwell
    Pharmacology and Toxicology, Georgia Regents University, Augusta, GA
  • Massoud Motamedi
    Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX
    Center for Biomedical Engineering, University of Texas Medical Branch, Galveston, TX
  • Ruth B Caldwell
    Vascular Biology Center, Georgia Regents University, Augusta, GA
    VA Medical Center, Augusta, GA
  • Wenbo Zhang
    Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX
    Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX
  • Footnotes
    Commercial Relationships Yonju Ha, None; Hua Liu, None; Zhimin Xu, None; Harumasa Yokota, None; Tahira Lemtalsi, None; Sylvia Smith, None; Robert William Caldwell, None; Massoud Motamedi, None; Ruth Caldwell, None; Wenbo Zhang, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2178. doi:https://doi.org/
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      Yonju Ha, Hua Liu, Zhimin Xu, Harumasa Yokota, Tahira Lemtalsi, Sylvia B Smith, Robert William Caldwell, Massoud Motamedi, Ruth B Caldwell, Wenbo Zhang; Endoplasmic Reticulum Stress-regulated CXCL10/CXCR3 pathway mediates inflammation and neuronal injury after retinal ischemia. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2178. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Retinal ischemia causes many vision threatening diseases including glaucoma, diabetic retinopathy, retinal vascular occlusion, etc. Mechanisms of neuronal injury caused by retinal ischemia remain to be defined. CXCL10 is a chemokine which induces recruitment and activation of inflammatory cells after binding to its receptor CXCR3. The CXCL10/CXCR3 is involved in tissue injury but its role in retinopathy is unknown. This study is to determine the role of CXCL10/CXCR3 pathway in neuronal injury after retinal ischemia.

Methods: Retinal ischemia-reperfusion (IR) was induced by increasing the intraocular pressure up to 110 mm Hg for 45 mins to block the retinal blood flow. Eye and retina were collected at 1 hr to 7 days after retinal ischemia and analyzed by qRT-PCR, immunohistochemistry and western blotting. 1°GCs were isolated from mice pups and were treated with 1, 10 and 100 ng/ml of CXCL10 for 24 hrs. Cell death was evaluated by TUNEL analysis. To investigate the relation between ER stress and CXCL10 expression, qRT-PCR was performed in in PBA or TUDCA treated retina after IR.

Results: Expressions of CXCL10 mRNA and protein were significantly increased at 6 hours after retinal ischemia. Blockade of the CXCL10/CXCR3 pathway by deleting CXCR3 gene significantly attenuated IR-induced upregulation of inflammatory molecules (IL-1β and E-selectin), inhibited recruitment of microglia/monocyte to the superficial retina, reduced peroxynitrite formation, and prevented loss of retinal ganglion cells. Treatment of 1°GCs to various doses of CXCL10 (1, 10 and 100 ng/ml) resulted in the dose dependent cell deaths (19.38±0.97%, 23.74±1.11% and 26.15±0.83 respectively). Additionally, IR-induced CXCL10 upregulation was associated with increases in ER stress related genes (GRP78, ATF4 and CHOP). Inhibition of ER stress with the PBA and TUDCA significantly decreased IR-induced CXCL10 expression in the retina.

Conclusions: These results indicate that activation of CXCL10/CXCR3 pathway has an essential role in retinal inflammation, oxidative stress and neuronal injury after retinal ischemia. ER stress is implicated in IR-induced upregulation of CXCL10.

Keywords: 572 ischemia • 426 apoptosis/cell death • 531 ganglion cells  
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