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Sean Silverman, Wenxin Ma, Lian Zhao, Wai T Wong; C3 deficiency results in accelerated rod photoreceptor loss in a mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3944.
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© ARVO (1962-2015); The Authors (2016-present)
The complement system has been implicated in multiple neurodegenerative diseases throughout the CNS, including the retina, and has been associated with both deleterious and neuroprotective effects. However, its role in influencing photoreceptor degeneration in retinitis pigmentosa (RP) is unclear. We examined photoreceptor degeneration in the rd10 mouse model of RP in which C3 has been genetically ablated.
rd10 mice bearing a pathogenic mutation in Pde6b were crossed with C3-deficient mice to generate C3+/+, C3+/-, C3-/- littermates in the rd10 background. Photoreceptor degeneration was monitored between post-natal day (P)16 and 30 using in vivo OCT and ERG assessments, and retinas analyzed for complement mRNA and protein expression, ONL thickness, TUNEL positivity, and microglial infiltration and activation.
rd10 retinas demonstrated significant upregulation of mRNA expression of alternative complement pathway components (C3), regulatory factors (CFB, CFH, CFI), and receptors (CR3, C3aR, C5aR), many upon the onset of photoreceptor degeneration at P21. Increased immunopositivity to Cfb and iC3b was localized to the degenerating outer retina, particularly to infiltrating microglia. Additionally, in situ hybridization localized increased C3 mRNA to infiltrating microglia. Deletion of one (C3+/-) or two (C3-/-) alleles of C3 in the rd10 background resulted in significantly accelerated degeneration relative to WT rd10 at P24 and P30, as assessed on OCT and histological evaluation. These differences were also correlated with significantly decreased ERG amplitudes at the same time points. Retinas from C3+/- and C3-/- animals also showed increased TUNEL labeling, increased density of infiltrating microglia, and elevated CD68 immunopositivity. C3+/- or C3-/- retinas did not show degeneration or microglial activation at P30 in the absence of rd10, and were quantitatively normal on OCT analysis.
Components of the complement cascade are prominently upregulated during rd10 photoreceptor degeneration, with C3 expression localizing significantly in infiltrating microglia. Deficiency of C3 in the rd10 context resulted in accelerated degeneration, indicating a protective role for C3. These findings have implications in the development of therapeutic agents modulating complement expression and activation in retinal diseases
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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