Disruption of the complement cascade delays retinal ganglion cell death following retinal ischemia-reperfusion.
Recent reports have indicated that components of the complement cascade are synthesized during the degeneration of retinal ganglion cells (RGC) in glaucoma. While complement deposition in the retina may simply serve to aid phagocytosis of damaged RGC, activation of the complement cascade can also contribute to neuronal loss in neurodegenerative diseases. This study was designed to determine if disruption of the complement cascade affects RGC survival in a murine model of retinal ischemia-reperfusion (I/R) injury. We induced retinal ischemia in the eyes of normal mice and mice with a targeted disruption of the complement component 3 (C3) gene. Tissue was harvested 7 and 21 days after induction of I/R and retinal complement synthesis was determined by quantitative PCR and immunohistochemical methods. RGC death and associated axon loss was evaluated through histological examination of the optic nerve and retina. Our data show that retinal I/R induces the expression and deposition of complement components. C3 deficient mice clearly exhibited reduced optic nerve damage and substantial preservation of RGC 1 week after I/R when compared to normal animals (p=0.005). Three weeks after the ischemic event C3 deficient mice retained more RGC cell bodies although the degree of optic nerve damage was similar between both groups. These findings demonstrate that inhibition of the complement cascade delays optic nerve axonal and RGC degeneration in retinal I/R. It appears that injured RGC are targeted and actively destroyed through complement mediated processes. These results may have implications for the pathophysiology and clinical management of ischemic retinal conditions.
Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA 52242, USA. markus-kuehn@uiowa.edu
Markus H
MH
Kuehn
Chan Y
CY
Kim
Bing
B
Jiang
Alina V
AV
Dumitrescu
Young H
YH
Kwon
D000818:Animals; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009900:Optic Nerve / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D012162:Retinal Degeneration / Q000276:immunology* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000473:pathology*
D003176:Complement C3