Natural killer cells promote neutrophil extracellular traps and restrain macular degeneration in mice.

Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex-mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.

Genome-wide analysis of genetic pleiotropy and causal genes across three age-related ocular disorders.

Age-related macular degeneration (AMD), cataract, and glaucoma are leading causes of blindness worldwide. Previous genome-wide association studies (GWASs) have revealed a variety of susceptible loci associated with age-related ocular disorders, yet the genetic pleiotropy and causal genes across these diseases remain poorly understood. By leveraging large-scale genetic and observational data from ocular disease GWASs and UK Biobank (UKBB), we found significant pairwise genetic correlations and consistent epidemiological associations among these ocular disorders. Cross-disease meta-analysis uncovered seven pleiotropic loci, three of which were replicated in an additional cohort. Integration of variants in pleiotropic loci and multiple single-cell omics data identified that Müller cells and astrocytes were likely trait-related cell types underlying ocular comorbidity. In addition, we comprehensively integrated eye-specific gene expression quantitative loci (eQTLs), epigenomic profiling, and 3D genome data to prioritize causal pleiotropic genes. We found that pleiotropic genes were essential in nerve development and eye pigmentation, and targetable by aflibercept and pilocarpine for the treatment of AMD and glaucoma. These findings will not only facilitate the mechanistic research of ocular comorbidities but also benefit the therapeutic optimization of age-related ocular diseases.

Association of cigarette smoking with retinal thickness and vascular structure in an elderly Chinese population.

BACKGROUND: To explore the association of cigarette smoking with retinal thickness and vascular structure in an elderly Chinese population. METHODS: This cross-sectional study enrolled employees and retirees aged over 50 years at Tianjin University of Sport from October 2020 to December 2020. Information on smoking status and lifestyle was obtained using a detailed questionnaire. All participants underwent full ophthalmic examination. OCTA image was acquired. Vascular and the thickness parameters in central fovea and peripapillary parameters were automatically calculated. Multiple linear regression analyses were utilized to assess the association of smoking with retinal thickness and vascular structure after controlling potential confounders. RESULTS: Compared with non-smoking adults, current smokers (ß=-36.78; P = 0.01) and ever smokers (ß=-35.45; P = 0.00) tended to have thinner macular fovea. Cigarettes daily, pack-years of smoking and CSI were negatively related to macular thickness (cigarettes daily: ß=-1.43; pack-years: ß=-14.73; CSI: ß=-14.70), while they were positively associated with the circumference (cigarettes daily: ß=0.03; pack-years: ß=0.30; CSI: ß=0.31) and the area of FAZ (cigarettes daily: ß=0.01; pack-years: ß=0.07). CONCLUSIONS: Cigarette smoking seems associated with decreased macular fovea thickness and elevated circumference and area of the FAZ compared to non-smokers. Our data add to evidence of smoking on retinal thickness and the microvascular system in the macular area.