Macrophage Sult2b1 promotes pathological neovascularization in age-related macular degeneration.
Macrophage Sult2b1 promotes pathological neovascularization in age-related macular degeneration.
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DOI：
10.26508/lsa.202302020
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发表时间：
2023-11
影响因子：
4.4
通讯作者：
Sun, Xiaodong
中科院分区：
文献类型：
--
作者：
Wang, Yafang;Liu, Yang;Wang, Yan;Wu, Yidong;Chen, Zhixuan;Wang, Feng;Wan, Xiaoling;Wang, Fenghua;Sun, Xiaodong
Sult2b1缺乏通过抑制M2巨噬细胞极化和通过LXR-ABCA1 /G1途径促进胆固醇外流，从而减弱病理性新生血管。紊乱的免疫反应和胆固醇代谢与年龄相关性黄斑变性（AMD）有关，AMD是老年人失明的主要原因。SULT2B1是固醇磺化的关键酶，在炎症和胆固醇代谢中起重要作用。然而，SULT2B1在AMD中的作用和潜在机制迄今尚未被研究。在这里，我们报道SULT2B1在脉络膜新生血管病变的巨噬细胞中特异性表达。在体内和体外，缺乏Sutl2b1可通过抑制M2巨噬细胞活化显著减少渗漏面积，抑制病理性血管生成。从机制上讲，Sult2b1的缺失激活了LXRs，随后增加了M2巨噬细胞中ABCA1和ABCG1 （ABCA1/G1）介导的胆固醇外排。LXR抑制（GSK2033治疗）对Sult2b1−/−巨噬细胞逆转M2极化，降低细胞内胆固醇容量，促进病理性血管生成。与SULT2B1相反，甾醇脱硫酶STS通过激活LXR-ABCA1 /G1信号来阻断M2极化，从而保护脉络膜新生血管的发展。总的来说，这些数据揭示了与新生血管性AMD中巨噬细胞极化相关的胆固醇代谢轴。
Sult2b1 deficiency attenuates pathologic neovascularization by inhibiting M2 macrophage polarization and promoting cholesterol efflux via the LXR–ABCA1/G1 pathway. 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. Sutl2b1 deficiency significantly reduced leakage areas and inhibited pathological angiogenesis by inhibiting M2 macrophage activation in vivo and in vitro. Mechanistically, loss of Sult2b1 activated LXRs and subsequently increased ABCA1 and ABCG1 (ABCA1/G1)-mediated cholesterol efflux from M2 macrophages. LXR inhibition (GSK2033 treatment) in Sult2b1−/− 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.
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