Deficiency of CXCR3 Prevents Inflammation and Neuronal Damage in Retinal Ischemic Injury

Abstract

Purpose: : Retinal neuronal death is a common pathological feature of many vision threatening diseases, such as diabetic retinopathy, retinal vascular occlusion and glaucoma. Recent studies indicate that inflammation could influence crucial steps of tissue injury. The goal of this study is to determine the role of the chemokine receptor CXCR3, a critical mediator of leukocyte recruitment and activation, in the retinal neuronal injury.

Methods: : Retinal neuronal injury was studied with a mouse model of retinal ischemia-reperfusion (IR). IR injury was generated in C57/BL6 wild type (WT) and CXCR3-deficient mice by increasing the intraocular pressure to 110 mm Hg for 40 minutes followed by reperfusion. Bone marrow transplants were performed by administration of bone marrow cells of EGFP mice to lethally irradiated WT mice.

Results: : CXCL10 is a ligand for CXCR3. Its mRNA level was markedly elevated following IR with a peak increase (175.5±23.1 fold) at 6 hours after reperfusion. Immunoreactivity for CXCL10 protein was also increased by IR and was evident in retinal neurons including ganglion cells. Immunolocalization studies using IbaI, a microglia/macrophage marker, revealed a prominent increase in these cells within the inner retina at 24 hours after reperfusion. Bone marrow transplant experiments revealed that IbaI positive cells included monocytes from circulation and retinal local microglia. CD11b, a marker for monocyte/microglia activation, and levels of the inflammatory molecules interleukin-1 beta and E-selectin, were also significantly increased following IR. The above changes were associated with increases in peroxynitrite formation, retinal cell apoptosis and loss of neurons within the ganglion cell layer. These retinal alternations were significantly attenuated in CXCR3-deficient mice.

Conclusions: : These results indicate that CXCL10/CXCR3 pathway is upregulated and is critically involved in IR-induced inflammatory reactions, oxidative stress and neuronal damage.

Keywords: ischemia • inflammation • neuroprotection