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CD40 Mediates Retinal Inflammation and Neurovascular Degeneration¹

Jose-Andres C. Portillo^*, Jennifer Van Grol^*,, Ling Zheng, Genevieve Okenka^*, Katrin Gentil^*, Alejandra Garland^*, Eric C. Carlson^*, Timothy S. Kern^*,, and Carlos S. Subauste^2,*,,

^* Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and Veterans Administration Medical Center, Research Service 151, Cleveland, OH 44106

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. Retinal inflammation, loss of ganglion cells, and capillary degeneration were markedly attenuated in ischemic retinas of CD40^–/– mice. Up-regulation of NOS2 and COX2 after retinal ischemia were blunted in CD40^–/– mice. NOS2-COX-2 up-regulation in ischemic retinas from wild-type mice was at least in part explained by recruitment of NOS2⁺COX-2⁺ leukocytes. Up-regulation of KC/CXCL1 and ICAM-1 also required CD40. Retinal endothelial and Muller cells expressed CD40. Stimulation of these cells through CD40 caused ICAM-1 up-regulation and KC/CXCL1 production. Bone marrow transplant experiments revealed that leukocyte infiltration, ganglion cell loss, and up-regulation of proinflammatory 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 neurovascular degeneration. They support a model in which CD40 stimulation of endothelial and Muller cells triggers adhesion molecule up-regulation and chemokine production, promoting the recruitment of leukocytes that express NOS2/COX-2, molecules linked to neurovascular degeneration.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Juvenile Diabetes Research Foundation, National Institutes of Health Grants EY00300 and P30 EY11373, Medical Research Service of the Department of Veterans Affairs, the American Heart Association Ohio Valley Affiliate, and the Research to Prevent Blindness Foundation. J.-A.C.P. is a recipient of a postdoctoral fellowship from the Ohio Lions Eye Research Foundation.

² Address correspondence and reprint requests to Dr. Carlos S. Subauste, Department of Ophthalmology and Visual Sciences, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106. E-mail address: carlos.subauste{at}case.edu

³ Abbreviations used in this paper: NOS2, NO synthase 2; COX-2, cyclooxygenase-2; EGFP, enhanced green fluorescent protein; IOP, intraocular pressure; I/R, ischemia/reperfusion; KO, knockout; cMFI, corrected mean fluorescence intensity.