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Philipp Herrmann, Jill Cowing, Sidath E Liyanage, Koji Miura Nishiguchi, Ulrich F O Luhmann, Robin R Ali; Sustained elevated light exposure in mice leads to strain dependent dysregulation of the complement system in the eye. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6329.
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Polymorphisms in several genes of the complement system are associated with the development of age-related macular degeneration. To investigate how different genetic backgrounds influence the local complement responses in the eye we exposed three mouse strains to sustained elevated light as a non-invasive way to stimulate complement activation.
We used a constant 7 day light exposure with 1000 lux at animal level and compared exposed BALB/c, C57BL/6 and 129/Sv mice to littermates in normal housing conditions. In vivo cSLO and OCT imaging and immunohistochemical analysis were used to determine structural retinal changes. RTqPCR on RPE/choroidal and retinal dissections were performed to assess changes in the expression level of major complement factors and macrophage markers. Flow cytometry was used to correlate the findings to changes in the inflammatory cell population.
At the structural level, elevated light exposure led to significant (p≤0.008) reduced retinal thickness by in vivo OCT imaging in the superior (-27,5μm, 95%CI[-45,9 to -9,1]) and inferior (-26,3μm 95%CI[-44.3 to -8.4]) hemisphere of BALB/c mice. C57BL/6 and 129/Sv mice showed no significant thinning. On immunohistochemistry, BALB/c mice showed GFAP+ Müller cell activation and Iba1+ macrophage/microglial activation. These findings correlated with flow cytometry showing a significant (p<0.02) increase in CD11b+ F4/80+ Ly6C+ cell populations after light exposure in the BALB/c, but not C57BL/6 or 129/Sv mice. RTqPCR showed an increase of local complement expression in the retinal compartment but only minor changes in the RPE/choroidal compartment of BALB/c mice (retinal C3 12 fold, Cfb 17 fold p<0.003). C57BL/6 mice showed a significant increase in retinal Properdin (1.4 fold p<0.01) and 129/Sv in retinal Cfd (2.3 fold p<0.05). All lines showed a significant increase in the retinal expression of either Ccl2 (Balb/c 49 fold, 129/Sv 6.5 fold), CD11b (Balb/c 6 fold, C57BL/6 1.8 fold) and/or iNOS (BALB/c 2.5 fold, C57BL/6 1.8 fold, p<0.02).
This data reveals that strain dependent genetic differences determine the local complement response to sustained elevated light exposure. The close association of increased systemic immune cell markers with complement activation and tissue damage may support that these cells contribute to local ocular pathology in a vulnerable genetic environment.
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