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.

中文翻译：

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自然杀伤细胞促进中性粒细胞胞外陷阱并抑制小鼠黄斑变性


新生血管性年龄相关性黄斑变性（nvAMD）是老年人失明的主要原因。尽管已知 nvAMD 与局灶性炎症有关，但对控制这一过程的精确免疫成分的了解仍然有限。在这里，我们将自然杀伤 (NK) 细胞确定为浸润 nvAMD 患者和小鼠模型脉络膜新生血管 (CNV) 病变血管周围空间的重要淋巴细胞群。 Olink 蛋白质组分析和单细胞 RNA 测序与敲除研究相结合，证明 CC 趋化因子受体 5 (CCR5) 参与小鼠 CNV 位点的 NK 细胞募集和外渗。耗尽 NK 细胞或抑制激活受体 NK 2 组成员 D (NKG2D) 可抑制中性粒细胞胞外陷阱的形成，增加血管渗漏，并加剧病理性血管生成，表明 NK 细胞抑制该小鼠模型中的发病机制。年龄是 AMD 的最强危险因素，我们发现来自老年人类捐赠者的 NK 细胞表现出较低的细胞毒性表型。来自年老小鼠的 NK 细胞在 CNV 小鼠模型中表现出受损的保护作用。此外，白介素 2 复合物介导的 NK 细胞扩增改善了小鼠 CNV 的形成。总的来说，我们的研究强调 NK 细胞是 nvAMD 患者的潜在治疗靶点。