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. Editor's summary: Vision loss in the late stages of neovascular age-related macular degeneration (nvAMD) is mainly caused by the formation of new blood vessels in the choroid layer of the eye. Current therapeutic strategies to inhibit choroidal neovascularization (CNV) are only partially effective. Dong et al. used a CNV mouse model and tissue samples from patients with nvAMD to show that natural killer cells accumulated in the choroid layer of the diseased eye. Depletion of NK cells prevented NETosis, a process known to regulate vascular remodeling, and aggravated pathology in CNV mice. IL-2–mediated NK cell expansion curbed the development of CNV in mice, highlighting the protective effects of NK cells. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]