CD40 mediates retinal inflammation and neurovascular degeneration.
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.
Portillo
Jose-Andres C
JA
Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Van Grol
Jennifer
J
Zheng
Ling
L
Okenka
Genevieve
G
Gentil
Katrin
K
Garland
Alejandra
A
Carlson
Eric C
EC
Kern
Timothy S
TS
Subauste
Carlos S
CS
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
D019013:CD40 Antigens; D018836:Inflammation Mediators