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C. Subauste, J.-A. Portillo, L. Zheng, G. Okenka, J. Van Grol, T. Kern; CD40 Mediates Retinal Inflammation and Neuro-Vascular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3569.
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Retinopathies are major causes of visual impairment. We used a model of ischemic retinopathy to examine the role of CD40 in the pathogenesis of retinal injury.
Ischemia / reperfusion of the retina was induced by transient elevation of the intra-ocular pressure. Histological changes in the retina were assessed using PASH staining and immunohistochemistry. Real time PCR was used to examine expression of mRNA of pro-inflammatory molecules. Flow cytometry was used to study expression of CD40 and ICAM-1. Production of KC/CXCL1 was assessed by ELISA. Bone marrow transplants were performed by administration of bone marrow cells to lethally irradiated mice.
Retinal inflammation, loss of ganglion cells and capillary degeneration were markedly attenuated in ischemic retinas of CD40 knock-out mice. Upregulation of NOS2 and COX2 after retinal ischemia were blunted in CD40 knock-out mice. NOS2/COX-2 upregulation in ischemic retinas from wild-type mice was at least in part explained by recruitment of NOS2+/COX-2+ leukocytes. Upregulation of KC/CXCL1 and ICAM-1 also required CD40. Primary retinal endothelial and Muller cells expressed CD40. Stimulation of these cells through CD40 caused ICAM-1 upregulation and KC/CXCL1 production. Bone marrow transplant experiments revealed that leukocyte infiltration, ganglion cell loss and upregulation of pro-inflammatory molecules after retinal ischemia were dependent on CD40 expression in the retina and not peripheral blood leukocytes.
These studies identified CD40 as a regulator of retinal inflammation and neuro-vascular degeneration after retinal ischemia. They support a model where CD40 stimulation of endothelial and Muller cells triggers adhesion molecule upregulation and chemokine production promoting the recruitment of leukocytes that express NOS2/COX-2, molecules linked to neuro-vascular degeneration.
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