Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization

IF 9.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE

Angiogenesis Pub Date : 2024-03-18 DOI:10.1007/s10456-024-09909-9

Gideon Obasanmi, Manjosh Uppal, Jing Z. Cui, Jeanne Xi, Myeong Jin Ju, Jun Song, Eleanor To, Siqi Li, Wania Khan, Darian Cheng, John Zhu, Lyden Irani, Isa Samad, Julie Zhu, Hyung-Suk Yoo, Alexandre Aubert, Jonathan Stoddard, Martha Neuringer, David J. Granville, Joanne A. Matsubara

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引用次数: 0

Abstract

Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD.

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颗粒酶 B 降解细胞外基质，促进炎症和脉络膜新生血管形成

老年性黄斑变性（AMD）是老年人常见的视网膜神经退行性疾病。新生血管性黄斑变性（nAMD）是导致老年黄斑变性相关性失明的主要原因，它涉及脉络膜新生血管（CNV），抗血管生成治疗可抑制CNV。然而，目前的 CNV 治疗并不适用于所有 nAMD 患者。在此，我们研究了一种治疗 AMD 的新靶点。Granzyme B（GzmB）是一种丝氨酸蛋白酶，它通过降解细胞外基质（ECM）和紧密连接促进衰老、慢性炎症和血管通透性。细胞外 GzmB 在健康老化外视网膜脉络膜的视网膜色素上皮（RPE）和肥大细胞中增加。在表现出 nAMD 和 CNV 特征的供体眼中，GzmB 进一步增加。在这里，我们在 RPE-脉络膜外植体培养物中发现，外源性 GzmB 会降解 RPE-脉络膜 ECM，促进视网膜/脉络膜炎症和血管生成，同时减少抗血管生成因子血栓软骨素-1（TSP-1）。药理抑制 GzmB 或肥大细胞脱颗粒可显著减少脉络膜血管生成。与我们的体外研究数据一致，GzmB缺陷可减少激光诱导的小鼠CNV病变程度以及与年龄相关的视网膜电图（ERG）反应恶化。这些研究结果表明，靶向 GzmB（一种没有已知内源性抑制剂的丝氨酸蛋白酶）可能是抑制 nAMD 中 CNV 的一种潜在的新型治疗方法。

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来源期刊

Angiogenesis PERIPHERAL VASCULAR DISEASE-

CiteScore

21.90

自引率

8.20%

发文量

审稿时长

6-12 weeks

期刊介绍： Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.