Abstract 11144: CXCR3 Deletion Limits Leukocyte Infiltration and Neurologic Damage Induced by Ischemia-Reperfusion Injury
Ischemic stroke has been defined as an acute episode of neurologic dysfunction caused by focal ischemia in the brain, spinal cord or retina following interruption of blood flow. This definition highlights the importance of pathophysiological processes underlying ischemia-reperfusion (IR)-induced tissue injury. In particular, IR-induced inflammation in the CNS and blood stream, such as production of cytokines, chemokines, and leukocyte recruitment, could influence crucial steps of tissue injury. CXCL10 is a chemokine which interacts with its receptor CXCR3 to recruit and activate several types of leukocytes including macrophage/microglia and T cells. We used CXCR3-deficient and wild type mice (CXCR3-/-) in a model of retinal IR injury to study neurovascular injury in relation to the CXCL10/CXCR3 interaction and leukocyte recruitment. The transparent nature of retina and accessibility for neurological testing provides an excellent platform for analysis of these molecular events. Retinal IR injury was achieved by increasing the intraocular pressure to 110 mm Hg, which completely blocks retinal blood flow. After 45 min normal pressure was restored, allowing reperfusion. The contralateral eye served as sham control. IR caused prominent retinal injury as indicated by a significant increase in DNA fragmentation (8.3±0.7 fold) and complete loss of the b-wave of the electroretinogram. Levels of CXCL10 mRNA were 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 photoreceptor cells, interneurons and ganglion cells. Expression of the inflammatory molecules interleukin-1 beta and E-selectin was significantly increased by IR (10.0±1.6 fold and 93.6±10.4 fold respectively). Immunolocalization studies using IbaI, a microglia/macrophage marker, revealed a prominent increase in these cells within the inner retina 24 hours after reperfusion. CD11b, a marker for microglia activation, was also significantly increased following IR (5.9±1.3 fold). These retinal alternations were significantly attenuated in CXCR3-deficient mice. These results indicate that CXCR3 is an important inflammatory mediator in retinal IR injury.
- © 2011 by American Heart Association, Inc.