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Jiyang Cai, Jianbin Chen, Pei Xu, Zhen-Yang Zhao, Yingzi Cong, Yan Chen; Interleukin-17 (IL-17) in Models of Retinal and RPE Degeneration. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Interleukin-17 (IL-17) is a pleiotropic cytokine that can be either tissue destructive or protective under conditions of chronic inflammation. Increased expression of IL-17 receptor C (IL-17RC) has been reported in the retina of eyes with age-related macular degeneration. The main goal of the present study is to define the function of IL-17 in the posterior eye using mouse genetics approaches.
IL-17RC knockouts were crossed with either C57BL/6N mice that carry rd8 mutation in the Crb1 gene, or mice with deficiency in nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The resultant double mutant mice were used as model of retinal or RPE degeneration, respectively. Ocular phenotype was monitored by fundus imaging, fluorescein angiography (FFA), optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) in animals with single or double mutations for up to 10 months, and was further validated by histopathology. Retinal microglia/macrophages were isolated and measured for expression of genes involved in inflammation and angiogenesis by quantitative RT-PCR. Same panels of genes were analyzed in bone marrow-derived mouse macrophages co-cultured with RPE explants and treated with IL-17.
Mice carrying rd8 mutation developed localized retinal lesions in the inferior nasal quadrant of the fundus at 1 month, with limited progression over the next 8 months. Double mutant mice with IL-17RC knockout and rd8 exhibited markedly accelerated retinal degeneration with significant increases in the number, size and distribution of hyper-reflective lesions on OCT, and retinal and RPE pathology on histology sections. Spontaneous retinal neovascularization was detected by FFA and histology in IL-17RC-/-; rd8/rd8 mice. IL-17RC/Nrf2 double knockout mice showed RPE pathology and sub-retinal cell infiltration at 6 months, a time point when the eyes of single knockout mice were apparently normal. IL-17 treatment in cultured macrophages suppressed the expression of genes associated with M2 polarization.
The results suggest that IL-17 confers protection of retinal or RPE degeneration in two different models, likely via mechanisms that control polarized activation of retinal microglia/macrophages. (Supported by NIH grants EY 019706, EY 021937, the International Retinal Research Foundation and Ted Nash Long Life foundation)
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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