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2012 ; 53
(12
): 7684-92
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A novel role of complement in retinal degeneration
#MMPMID23074214
Yu M
; Zou W
; Peachey NS
; McIntyre TM
; Liu J
Invest Ophthalmol Vis Sci
2012[Nov]; 53
(12
): 7684-92
PMID23074214
show ga
PURPOSE: The association of single nucleotide polymorphisms of components of the
complement alternative pathway with the risk of age-related macular degeneration
(AMD) indicates that complement signaling plays an important role in retinal
physiology. How genetic variation leads to retinal degeneration is unknown. It
has been assumed that complement activation augments immune responses, which in
turn initiate AMD pathogenesis. To better understand the relationship between
complement and the outer retina, we examined mice lacking the main complement
component C3 and the receptors for complement activation fragments C3a (C3aR)
and/or C5a (C5aR). METHODS: Complement mutant mice were studied along with
wild-type (WT) littermates from 6 weeks to 14 months of age. Strobe flash
electroretinography (ERG) was used to examine outer retinal function and a dc-ERG
technique was used to measure ERG components generated by the retinal pigment
epithelium. Retinas were examined by histology, immunohistochemistry, and
biochemistry. RESULTS: Mice lacking C3aR and/or C5aR developed early onset and
progressive retinal degeneration, accompanied by cleaved caspase-3 upregulation.
Genetic deletion of C3aR and/or C5aR led to cell-specific defects that matched
the cellular localization of these receptors in the WT retina. Compared to WT,
C3aR(-/-) and C3aR(-/-)C5aR(-/-) mice showed increased retinal dysfunction upon
light exposure. C3aR(-/-)C5aR(-/-) mice immunized with 4-hydroxynonenal-adducted
protein developed severe retinal impairment unrelated to immune response.
CONCLUSIONS: C3aR- and C5aR-mediated signaling was necessary to maintain normal
retinal function and structure. These receptors may be important biomarkers for
predicting retinal degeneration including AMD.
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