Abstract：
One type of age-related macular degeneration (AMD), neovascular (nAMD), characterized by choroidal neovascularization (CNV), accounts for the majority of the severe central vision impairment associated with AMD. Endothelial cells (ECs) in direct contact with retinal pigment epithelial (RPE) cells are more prone to the pathological angiogenesis involved in CNV. Herein, we investigated the effect of crosstalk between RPE cells and choroidal endothelial cells (CECs) via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis on the development of choroidal neovascularization (CNV) in vitro and in vivo. ANXA1 expression and secretion from ARPE-19 cells were upregulated by hypoxia. FPR2 expression, especially on the plasma membrane, in HCECs was upregulated under hypoxic conditions. ANXA1 secreted from ARPE-19 cells inhibited NLRP3 inflammasome activation and NLRP3 inflammasome-mediated pyroptosis in HCECs by activating the FPR2/SHP2 axis. Moreover, ANXA1 secreted by ARPE-19 cells promoted behaviors of HCECs, including proliferation, migration, and tube formation, by activating the FPR2/SHP2 axis and inhibiting NLRP3 inflammasome-mediated pyroptosis. Inhibiting the upregulated ANXA1/FPR2/SHP2/NLRP3 inflammasome/pyroptosis axis decreased the volume of CNV. Our data suggest that the crosstalk between RPE cells and CECs via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis promotes CNV. This finding could identify a potential target for the prevention and treatment of CNV.
摘要：
一种年龄相关性黄斑变性（AMD），新生血管（nAMD），以脉络膜新生血管（CNV）为特征，占与AMD相关的严重中央视力障碍的大部分。与视网膜色素上皮（RPE）细胞直接接触的内皮细胞（ECs）更容易发生与CNV有关的病理性血管生成。在这里，我们在体外和体内研究了RPE细胞和脉络膜内皮细胞（CECs）之间通过ANXA1/FPR2/NLRP3炎性体/焦亡轴的串扰对脉络膜新生血管（CNV）发展的影响。ARPE-19细胞的ANXA1表达和分泌被缺氧上调。FPR2表达式,尤其是在质膜上，在缺氧条件下，HCECs的表达上调。ARPE-19细胞分泌的ANXA1通过激活FPR2/SHP2轴抑制HCECs中NLRP3炎性体活化和NLRP3炎性体介导的细胞凋亡。此外，ARPE-19细胞分泌的ANXA1促进HCECs的行为，包括扩散，迁移,和管的形成，通过激活FPR2/SHP2轴并抑制NLRP3炎性体介导的焦亡。抑制上调的ANXA1/FPR2/SHP2/NLRP3炎性体/焦度轴降低CNV的体积。我们的数据表明，RPE细胞和CEC之间通过ANXA1/FPR2/NLRP3炎性体/焦亡轴的串扰促进CNV。这一发现可以确定预防和治疗CNV的潜在靶标。
