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TPC2 促进了新生血管性年龄相关性黄斑变性小鼠模型脉络膜血管生成和炎症。

TPC2 promotes choroidal angiogenesis and inflammation in a mouse model of neovascular age-related macular degeneration.

机构信息

Department of Pharmacy, Ludwig-Maximilians-Universität München, München, Germany.

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.

出版信息

Life Sci Alliance. 2021 Jun 28;4(8). doi: 10.26508/lsa.202101047. Print 2021 Aug.

DOI:10.26508/lsa.202101047
PMID:34183443
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8321671/
Abstract

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly and can be classified either as dry or as neovascular (or wet). Neovascular AMD is characterized by a strong immune response and the inadequate release of cytokines triggering angiogenesis and induction of photoreceptor death. The pathomechanisms of AMD are only partly understood. Here, we identify the endolysosomal two-pore cation channel TPC2 as a key factor of neovascularization and immune activation in the laser-induced choroidal neovascularization (CNV) mouse model of AMD. Block of TPC2 reduced retinal VEGFA and IL-1β levels and diminished neovascularization and immune activation. Mechanistically, TPC2 mediates cationic currents in endolysosomal organelles of immune cells and lack of TPC2 leads to reduced IL-1β levels in areas of choroidal neovascularization due to endolysosomal trapping. Taken together, our study identifies TPC2 as a promising novel therapeutic target for the treatment of AMD.

摘要

年龄相关性黄斑变性（AMD）是老年人失明的最常见原因，可分为干性或新生血管性（湿性）。新生血管性 AMD 的特征是强烈的免疫反应和细胞因子的释放不足，触发血管生成和光感受器死亡。AMD 的发病机制尚不完全清楚。在这里，我们确定内溶酶体双孔阳离子通道 TPC2 为 AMD 的激光诱导脉络膜新生血管（CNV）小鼠模型中新生血管形成和免疫激活的关键因素。TPC2 的阻断减少了视网膜 VEGFA 和 IL-1β 水平，并减少了新生血管形成和免疫激活。从机制上讲，TPC2 在免疫细胞的内溶酶体细胞器中介导阳离子电流，缺乏 TPC2 会导致脉络膜新生血管化区域的 IL-1β 水平因内溶酶体捕获而降低。总之，我们的研究将 TPC2 确定为治疗 AMD 的有前途的新治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd3/8321671/29ebfb9e095e/LSA-2021-01047_Fig9.jpg
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