Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, China.
Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Sci Transl Med. 2024 Aug 14;16(760):eadi6626. doi: 10.1126/scitranslmed.adi6626.
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.
新生血管性年龄相关性黄斑变性（nvAMD）是老年人致盲的主要原因。尽管已知 nvAMD 与局灶性炎症有关，但对于控制这一过程的确切免疫成分的理解仍然有限。在这里，我们发现自然杀伤 (NK) 细胞是一种突出的淋巴细胞群，浸润 nvAMD 患者和小鼠模型脉络膜新生血管 (CNV) 病变的血管周围空间。Olink 蛋白质组分析和单细胞 RNA 测序结合敲除研究表明，C-C 趋化因子受体 5 (CCR5) 参与了 NK 细胞在 CNV 部位的募集和渗出。NK 细胞耗竭或抑制激活受体 NK 组 2，成员 D (NKG2D) 抑制中性粒细胞细胞外陷阱的形成，增加血管渗漏，并加剧病理性血管生成，表明 NK 细胞在该小鼠模型中抑制发病机制。年龄是 AMD 的最强危险因素，我们表明来自老年供体的 NK 细胞表现出较少的细胞毒性表型。老年小鼠的 NK 细胞在 CNV 小鼠模型中表现出受损的保护作用。此外，白细胞介素-2 复合物介导的 NK 细胞扩增改善了小鼠的 CNV 形成。总之，我们的研究强调了 NK 细胞作为 nvAMD 患者的潜在治疗靶点。
