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Autophagy in age-related macular degeneration using Vldlr KO mouse model of retinopathy

ABSTRACT: Autophagy plays vital housekeeping neuronal functions but is not believed to fuel energy metabolism. Autophagy regulation by lipids nutrient sensors have not been identified. Cone photoreceptors’ very-low-density lipoprotein receptor (Vldlr) expression facilitates the uptake of triglyceride-derived fatty acid. In Vldlr-/- mice, we identify free fatty acid receptor 1 (Ffar1) as a suppressor of transcription factor EB (Tfeb), a master regulator of autophagy. Tfeb, in turn, governs the expression of PGC1 and Sirtuin-3, leading to reduced -ketoglutarate (-KG). We recently showed that low -KG in Vldlr-/- photoreceptors drives Vegfa expression and neovascularization reminiscent of a subset of age-related macular degeneration (AMD). Metabolomics of human AMD vitreous and Vldlr-/- retinas identified a similar Krebs cycle metabolite signature. Improving autophagy in AMD-like mice rescued the neovascular phenotype and vision. Dysregulated autophagy may therefore compound the energy failure of photoreceptors contributing to neovascular AMD and could be a driving force in other neovascular diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE110623 | GEO | 2022/02/24

REPOSITORIES: GEO

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Project description:Objective: Retinal angiomatous proliferation (RAP) represents a special form of neovascular age-related macular degeneration. Immune cells accumulate at RAP, but so far it is unclear whether these cells are resident retinal microglial cells (MG) or blood infiltrating monocytes (MO) and whether these cells can influence RAP formation. The aim of this study is to determine the relative contribution of MG and MO to RAP and to define the transcriptional profile of the dominant cell population. Methods: Vldlr -/- Knockout mice were crossed with MG-specific Cx3cr1CreER/+:Rosa26-Tomfl/+ re-porter mice (MG-Tom). The resulting Vldlr-/-:MG-Tom mice received tamoxifen injection at day 1 after birth (P1), leading to expression of Tomato fluorochrome (Tom) in myeloid cells. Myeloid cells were examined at P17, P31, and P42 by immunohistochemical Iba1 staining and retinal Tom expression. In addition, Tom-positive MG were isolated at P17 by fluorescence-activated cell sorting, and the transcriptional profile of MG was analyzed by RNA sequencing. MG Tom mice, also injected at P1 with tamoxifen, served as controls for RNA-Seq. Results: Our data show that at the beginning of RAP formation (P17), hardly any MO migrates from blood into tissues (0.2±0.5 MO/RAP, 2.0±0.8 MG/RAP). During the course of RAP formation, this changes only slightly (P31: 0.6±2.2 MO/RAP, 10.3±12.8 MG/RAP; P42: 0.6±2.4 MO/RAP, 14.3±9.4 MG/RAP). RNA sequencing of the isolated MG identified 140 differentially expressed genes (DEG), of which 67 were upregulated and 73 were downregulated upon RAP formation. Gene ontology enrichment analysis of the 140 DEGs revealed that they contribute primarily to immune-associated processes, such as leukocyte migration and chemotaxis, regulation of the immune system and immune response, and wound responses. Retinal MG thereby express the pro-angiogenic soluble factor Spp1 (log2FC 1.8) in addition to Ccl2 and Cxcl14 during RAP formation. Conclusion: Our data indicate that resident MG represent the dominant immune cell population during retinal angiomatous proliferation in the Vldlr knockout mouse. RNA sequencing of MG reveals upregulation of immune-associated processes and of pro-angiogenic factors, such as Spp1. Cell-specific modulation of MG may thus form the basis of a future therapeutic option for the treatment of RAP.

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Autophagy in age-related macular degeneration using Vldlr KO mouse model of retinopathy

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