Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Medical Research Center, Peking University Third Hospital, Beijing, China.
Life Sci Alliance. 2023 Aug 7;6(11). doi: 10.26508/lsa.202302020. Print 2023 Nov.
Disordered immune responses and cholesterol metabolism have been implicated in age-related macular degeneration (AMD), the leading cause of blindness in elderly individuals. SULT2B1, the key enzyme of sterol sulfonation, plays important roles in inflammation and cholesterol metabolism. However, the role and underlying mechanism of SULT2B1 in AMD have not been investigated thus far. Here, we report that SULT2B1 is specifically expressed in macrophages in choroidal neovascularization lesions. deficiency significantly reduced leakage areas and inhibited pathological angiogenesis by inhibiting M2 macrophage activation in vivo and in vitro. Mechanistically, loss of activated LXRs and subsequently increased ABCA1 and ABCG1 (ABCA1/G1)-mediated cholesterol efflux from M2 macrophages. LXR inhibition (GSK2033 treatment) in macrophages reversed M2 polarization and decreased intracellular cholesterol capacity to promote pathological angiogenesis. In contrast to SULT2B1, STS, an enzyme of sterol desulfonation, protected against choroidal neovascularization development by activating LXR-ABCA1/G1 signalling to block M2 polarization. Collectively, these data reveal a cholesterol metabolism axis related to macrophage polarization in neovascular AMD.
免疫反应紊乱和胆固醇代谢与年龄相关性黄斑变性（AMD）有关，AMD 是导致老年人失明的主要原因。磺基转移酶 2B1（SULT2B1）是固醇硫酸化的关键酶，在炎症和胆固醇代谢中发挥重要作用。然而，SULT2B1 在 AMD 中的作用和潜在机制迄今尚未得到研究。在这里，我们报告 SULT2B1 特异性表达于脉络膜新生血管病变的巨噬细胞中。 缺失显著减少了渗漏面积，并通过抑制体内和体外 M2 巨噬细胞的活化来抑制病理性血管生成。在机制上，缺失 激活了 LXRs，随后增加了 ABCA1 和 ABCG1（ABCA1/G1）介导的 M2 巨噬细胞中的胆固醇外流。在 巨噬细胞中抑制 LXR（GSK2033 处理）逆转了 M2 极化并降低了细胞内胆固醇容量，从而促进病理性血管生成。与 SULT2B1 相反，固醇脱硫酶 STS 通过激活 LXR-ABCA1/G1 信号通路来阻止 M2 极化，从而保护脉络膜新生血管免于发生。总之，这些数据揭示了与新生血管 AMD 中巨噬细胞极化相关的胆固醇代谢轴。
