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Immune Modulation of Macular Degeneration Through Natural Killer Cell Activity

ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the world and can result in pathological neovascularization in late-stage disease. Discovery of new processes of disease pathogenesis are needed, as current gold-standard treatments have a therapeutic ceiling. Here we used a ‘human-first’ approach to uncover underlying mechanisms of disease and in doing so identify immunotherapy as a potential disease modifier for AMD. Plasma cytokine analysis in The Irish Longitudinal stuDy on Ageing (TILDA), a large-scale population cohort, revealed an imbalance of peripheral lymphocytic type 1 and type 2 signature cytokines associated with severity of AMD. This led us to discover a skewed phenotype for innate lymphoid Natural Killer (NK) cells, but not T lymphocytes, in the peripheral blood of people with AMD, indicating peripheral NK cells may modulate retinal disease. Modelling retinal injury using a laser, we confirmed splenic NK cells were activated in response to distal retinal injury, with concordance between mouse and human lymphocytic activation patterns. scRNA-sequencing demonstrated expansion of a defined subset of activated cytolytic NK cells at the neovascular lesion site and found that NK cell proliferation, biogenesis and metabolic respiration is heightened during active resolution of retinal neovascular lesions. We find that NK cells play a critical role in remodelling neovascular lesions through their cytotoxic activity, limiting pathology. We find NK cells localize to the basolateral side of neovessels in human AMD donor eye tissue and show that primary human retinal endothelial cells can act as target cells for NK cell-directed cytolysis. NK cells in both peripheral blood and donor eye tissue exhibit a variety of markers of NK cell quiescence in AMD and indicate NK cells have limited capacity for replenishment at the site of disease, which may be a factor in disease progression. Adoptive NK cell immunotherapy with cytokine-activated NK cells reduces neovascular lesion volume and repairs neovessel barrier integrity in models of retinal neovascularization. Here, we propose that harnessing NK cells may represent a novel transformative therapeutic strategy for the prevention and treatment of neovascular eye disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE317763 | GEO | 2026/05/06

REPOSITORIES: GEO

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Project description:Background Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Recent studies have demonstrated strong genetic associations between AMD and single nucleotide polymorphisms (SNPs) within genes such as CFH and HTRA1. However, we have identified monozygotic twins discordant for AMD phenotypes (one with disease, the other without disease), suggesting that an epigenetic mechanism may also contribute to the pathogenesis of AMD. Methods We identified two twin pairs with phenotypic discordance of AMD. We obtained genomic DNA from their peripheral blood mononuclear cells (PBMCs) and subjected them to DNA methylation-chip analysis (MeDIP-chip) that profiled genome-wide DNA methylation patterns on promoters of all genes and microRNAs. We next utilized the Methyl-Profiler DNA methylation assays to detect the methylation status of selected promoters. Flow cytometry and quantitative real-time PCR were used to detect the expression of the selected gene in peripheral blood cells, as well as in retinal and choroidal tissues of AMD patients and non-AMD controls. Results Our MeDIP-chip analysis identified 256 genes with hypo-methylated promoters only in the twins with AMD and 744 genes with hyper-methylated promoters only in the twins with AMD. Importantly, the promoter region of IL17RC was associated with hypo-methylated CpG sites only in the twins with AMD but not in the twins without AMD. We also found the association of the hypo-methylated IL17RC promoter with AMD in 7 pairs of siblings with discordant AMD pathology (P=0.003), as well as an independent patient cohort (95 neovascular wet and 107 geographic atrophy dry AMD patients as well as 96 non-AMD controls (95% CI, 0.01-0.10, P=9.8x10-8 for wet AMD vs. control; 95% CI, 0.05-0.32, P=2.2x10-5 for dry AMD vs. control)). Interestingly, we did not find an association between the levels of methylation on the IL17RC promoter with the previously identified genetic risk alleles in CFH, HTRA1, and ARMS2. We demonstrated an elevated expression of the IL-17RC protein in CD14+ monocytes in the peripheral blood of AMD patients as compared to non-AMD controls. These IL-17RC+ monocytes have elevated expression of CXCR1, CXCR2, and CXCR4. In addition, IL17RC was expressed only in the retinal and choroidal tissues from AMD patients but not from age-matched controls. Conclusions We show an association of the hypo-methylated IL17RC promoter with AMD, which resulted in the elevated expression of IL-17RC in peripheral blood cells as well as the retinal and choroidal tissues of AMD patients. Our study suggests that the hypo-methylated IL17RC promoter and elevated expression of IL-17RC can potentially serve as biomarkers for the diagnosis of AMD, while IL-17RC can be a new therapeutic target for AMD. In addition, our results strongly suggest an epigenetic control mechanism of AMD pathogenesis. The Affymetrix MOE430 2.0 GeneChip was used to detect gene expression patterns within the whole eye of C57B/6 normal mice.

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Immune Modulation of Macular Degeneration Through Natural Killer Cell Activity

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