title: CD40 mediates retinal inflammation and neurovascular degeneration.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Jose-Andres C
authors.initials: JA
authors.lastname: Portillo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Van Grol
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
authors.forename: Genevieve
authors.initials: G
authors.lastname: Okenka
authors.forename: Katrin
authors.initials: K
authors.lastname: Gentil
authors.forename: Alejandra
authors.initials: A
authors.lastname: Garland
authors.forename: Eric C
authors.initials: EC
authors.lastname: Carlson
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Subauste
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D018836:Inflammation Mediators