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H. Xu, M. Chen, J. V. Forrester, A. D. Dick; Inflammation-Induced Retinal Angiogenesis in Experimental Autoimmune Uveoretinitis in C57BL/6 Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5785.
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Experimental autoimmune uveoretinitis (EAU) in C57BL/6 mice was thought to be a self-limiting chronic retinal inflammation model. In an attempt to understand how the retina might recover after inflammation, we investigated retinal changes 2-4 months after EAU induction in this mouse strain. Surprisingly, retinal inflammation did not resolve but instead persistent chronic inflammation induced focal retinal angiogenesis.
8~12-week C57BL/6 mice were immunized s.c. with 500 µg IRBP peptide 1-20 emulsified in CFA, with an additional i.p injection of 1.5 µg of pertussis toxin. Retinal inflammation was monitored with topical endoscopic fundus imaging (TEFI) system from day 18-30 post-immunization (p.i.). Mice with retinal inflammation were followed for a period and examined on days 60, 80, and120 p.i., by TEFI, conventional histology and confocal microscopy of retinal flatmounts. Splenocytes cytokine production was evaluated by cytokine bead assay.
Following the initial severe inflammation (day 21~30 p.i.), the severity of retinal inflammation declined rapidly and chronic inflammation persisted. The chronic phase retinal inflammation lasted for over 4 months, and did not completely resolve during the experimental period. Features in the chronic phase include vascular cuffing, multifocal choroidal lesions, vitreous infiltrates as aggregations (snow balls), retinal neovascular membranes and retinal atrophy. There is a heterogeneous inflammatory infiltrate in late stage EAU consisting of CD4+ T cells, CD68+MHC-II+ and CD68-arginase-1+ macrophages. IRBP-peptide activated splenocytes from day 80 p.i. EAU mice still generated IL-17 equivalent to those from day 30 p.i. EAU mice but unable to generate IFN-γ. Confocal microscopy of retinal flatmounts of day 80 p.i. EAU mice revealed multiple intraretinal neovascular complexes, arising from retinal venules and post-capillary veunles. As disease progressed retinal neovascular membranes extended towards RPE layer associated with RPE detachment.
Inflammation in EAU C57BL/6 mice persists with changes in macrophage profile, associated with induction of revascularization. The model provides a unique opportunity to study mechanisms of, and to test treatments for, inflammation-induced angiogenesis.
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