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Zhen-Yang Zhao, Pei Xu, Yiqin Zuo, Bo Yu, Bo Long, Yan Chen, Jiyang Cai; T Cells Infiltration and RPE Degeneration in NRF2-deficient Mice Fed with High Fat, Cholesterol-Rich Diet. Invest. Ophthalmol. Vis. Sci. 2014;55(13):75.
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Interleukin-17 (IL-17) producing T cells play crucial roles in the etiology of various autoimmune and chronic degenerative diseases. Recent genetic study has shown hypomethylation of the IL17RC gene in patients with age-related macular degeneration (AMD), indicating that IL-17 signaling is involved in its pathogenesis. The purpose of this study is to characterize the infiltration of T lymphocytes and their production of IL-17 in the choroid and retina of NRF2-deficient mice fed with high fat, cholesterol-rich diet (HF-C).
Both B6.129 wild-type and Nrf2-/- mice at 12 months of age were fed with either standard rodent chow (ND) or HF-C diet, with 5% and 20% (w/w) fat, respectively. The HF-C diet also contained 0.15% cholesterol. Fundus phenotype of each group was monitored by optical coherence tomography (OCT) and scanning laser ophthalmoscope, and confirmed by retinal histopathology. Immunostaining of cryosections, retinal and RPE flat mounts were employed to study the cell infiltration. Flow cytometry was used to investigate the subsets of intraocular lymphocytes.
After 16-week HF-C treatment, OCT scan revealed that 58% of the eyes from Nrf2-/- mice had progression of retinal lesions. RPE degeneration and choroidal neovascularization were evident on paraffin sections, with only moderate photoreceptor loss. Foxp3+ regulatory T cells (Tregs) and CD3+ IL-17 producing T cells were detected in the retina and choroid, respectively. Flow cytometry data further revealed that the amount of Tregs decreased in Nrf2-/- mice after receiving the HF-C diet; however, a 3-fold increase of IL-17+ cells, most of which were CD3+ CD4- TCRγδ+ cells, was observed in Nrf2-/- HF-C mice comparing to WT HF-C mice.
Feeding HF-C diet to 12-month old Nrf2-/- mice exacerbated the RPE degeneration. The increase of microglias, γδ-T cells and decreased Tregs in the choroid and retina promoted chronic inflammation and contribute to the progression of AMD-like phenotypes in these animals.
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