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Role of NR4A1 and non-classical monocytes in a mouse model of neovascular age-related macular degeneration

ABSTRACT: Role of NR4A1 and non-classical monocytes in a mouse model of neovascular age-related macular degeneration

PROVIDER: PRJNA1001664 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25501380_1.fastq.gz	Fastqsanger.gz
	SRR25501380_2.fastq.gz	Fastqsanger.gz
	SRR25501381_1.fastq.gz	Fastqsanger.gz
	SRR25501381_2.fastq.gz	Fastqsanger.gz
	SRR25501382_1.fastq.gz	Fastqsanger.gz

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Role of NR4A1 and non-classical monocytes in a mouse model of neovascular age-related macular degeneration

Project description:Neovascular AMD (nAMD) causes vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Cx3cr1-/- mice display non-classical monocyte and microglia alterations, and increased CNV size, suggesting that non-classical monocytes may inhibit CNV formation. While Nr4a1-/- mice are deficient in non-classical monocytes, results are confounded by macrophage hyper-activation. Nr4a1se2/se2 mice lack a transcriptional activator, resulting in non-classical monocyte loss, without macrophage hyper-activation. We subjected Nr4a1-/- and Nr4a1se2/se2 mice to the laser-induced CNV model and performed multi-parameter flow cytometry. We found that both models lack non-classical monocytes, but only Nr4a1-/- mice displayed increased CNV area. Additionally, CD11c+ macrophages were increased in Nr4a1-/- mice. Single-cell transcriptomic analysis uncovered that CD11c+ macrophages were enriched from Nr4a1-/- mice and expressed a pro-angiogenic transcriptomic profile that was disparate from prior reports of macrophage hyper-activation. These results suggest that non-classical monocytes are dispensable during laser-induced CNV, and NR4A1 deficiency shifts the transcriptional profile toward a pro-angiogenic phenotype.

2024-02-28 | GSE239941 | GEO

Total blood monocyte gene expression from neovascular age-related macular degeneration patients and age-matched controls

Project description:Mononuclear phagocytes (MPs), including monocytes and macrophages, play complex roles in the pathogenesis of age-related macular degeneration (AMD). We aimed to perform global transcriptome analysis on monocytes from AMD patients to obtain additional insight to the role of MPs in AMD. Peripheral blood was taken from treatment-naïve neovascular AMD (nvAMD) patients (n=14), and age-matched controls (n=15). Peripheral blood mononuclear cells (PBMCs) were separated and monocytes were isolated via negative selection. Gene expression was evaluated with Affymetrix Gene1.0 ST microarrays. Statistical/bioinformatics analysis was performed using open sourceware programs.

2017-02-10 | GSE76237 | GEO

Impaired RPE Mitochondrial Energetics Leads Subretinal Fibrosis in Neovascular Age-related Macular Degeneration

Project description:Impaired RPE Mitochondrial Energetics Leads Subretinal Fibrosis in Neovascular Age-related Macular Degeneration

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Impaired RPE Mitochondrial Energetics Leads Subretinal Fibrosis in Neovascular Age-related Macular Degeneration

Project description:Subretinal fibrosis permanently impairs the vision of patients with neovascular age-related macular degeneration. Despite emerging evidence revealing the association between disturbed metabolism in retinal pigment epithelium (RPE) and subretinal fibrosis, the underlying mechanism remains unclear. In the present study, single-cell RNA sequencing revealed, prior to subretinal fibrosis, genes in mitochondrial fatty acid oxidation are downregulated in the RPE lacking very low-density lipoprotein receptor (VLDLR), especially the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). We found that overexpression of CPT1A in the RPE of Vldlr-/- mice suppresses epithelial-to-mesenchymal transition and fibrosis. Mechanistically, TGFβ2 induces fibrosis by activating a Warburg-like effect, i.e. increased glycolysis and decreased mitochondrial respiration through ERK-dependent CPT1A degradation. Moreover, VLDLR blocks the formation of the TGFβ receptor I/II complex by interacting with unglycosylated TGFβ receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGFβ2-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis.

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Transcriptomic Characterization of Human Choroidal Neovascular Membranes Identifies Calprotectin as a Novel Biomarker for Patients with Age-related Macular Degeneration

Project description:Although genome-wide association studies, animal models, and cell culture systems have yielded important insights into the pathogenesis of neovascular age-related macular degeneration (nAMD), the underlying molecular pathways remain ill defined. Recent studies have deciphered the transcriptional profile of choroidal neovascularisation (CNV) of body donor eyes and were thus limited by the time span from death to preservation and the associated rapid 5'-RNA degradation. In this study, CNVs were therefore formalin-fixed immediately after surgical extraction from patients with nAMD and analyzed using a 3’ RNA sequencing approach called Massive Analysis of cDNA Ends (MACE). Age-matched formalin-fixed paraffin-embedded (FFPE) RPE-choroidal specimens obtained from the macular region of enucleated eyes with ciliary body melanoma served as controls. Transcriptome profiles were generated and disease-associated gene signatures were identified using statistical and bioinformatic methods. Calprotectin (S100A8/A9) protein expression was investigated by immunohistochemistry and ELISA.We identified 158 differentially-expressed genes (DEG) that were significantly increased in CNV compared to control tissue. Gene ontology enrichment analysis demonstrated that these DEG contributed to biological processes, such as Blood Vessel Development, Extracellular Structure Organization, Response to Wounding and several immune-related terms. The S100 calcium-binding protein A8 (S100A8) and S100A9 emerged among the top DEG, as confirmed by immunohistochemistry on CNV tissue and protein analysis of vitreous samples from nAMD patients and controls. This study provides a high-resolution RNA-sequencing-based transcriptional signature of choroidal neovascular membranes in AMD patients and reveals S100A8/A9 as a novel biomarker and promising target for AMD-directed therapeutics and diagnostics.

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Natural killer cells cooperate with neutrophils to suppress pathological angiogenesis in neovascular age-related macular degeneration

Project description:Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population associated with focal inflammation, however, understanding of the precise immune components governing this process is still limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions. O-link analysis and single-cell RNA sequencing approaches identified CCR5-expressing NK cells is essential for further NK cell recruitment and extravasation in CNV site. NK cells suppress pathological angiogenesis via through clearance of senescent vasculatures, a process that requires neutrophil extracellular traps (NETs). Mechanistically, the release of NETs results from NKG2D-dependent NK cell activation and production of IFN-γ at CNV lesions. Notably , age is the strongest risk factor for AMD to an aged immune system; our human and mouse data showed that aged NK cells exhibited compromised protective effects. Additionally, expansion of NK cells by IL-2 complex improved CNV formation. Collectively, our results revealed a previously unrecognized role of NK cells in suppressing nvAMD progression, suggesting these cells as a potential target for future immune therapies for patients with nvAMD.

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Natural killer cells cooperate with neutrophils to suppress pathological angiogenesis in neovascular age-related macular degeneration

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Epigenetic Regulation of IL17RC in Age-related Macular Degeneration

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Project description: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.

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Natural killer cells cooperate with neutrophils to suppress pathological angiogenesis in neovascular age-related macular degeneration [scRNA-seq]

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