Cheng Xinxuan, He Danxue, Liao Chunyan, Lin Sijie, Tang Liying, Wang Yuan-Liang, Hu Jiaoyue, Li Wei, Liu Zuguo, Wu Yalin, Liao Yi
Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Eye Institute of Xiamen University, Xiamen University, Xiamen, China.
Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, China.
J Cell Physiol. 2021 May;236(5):3660-3674. doi: 10.1002/jcp.30103. Epub 2020 Oct 9.
The underlying mechanisms of complement activation in Stargardt disease type 1 (STGD1) and age-related macular degeneration (AMD) are not fully understood. Overaccumulation of all-trans-retinal (atRAL) has been proposed as the pathogenic factor in both diseases. By incubating retinal pigment epithelium (RPE) cells with atRAL, we showed that C5b-9 membrane attack complexes (MACs) were generated mainly through complement alternative pathway. An increase in complement factor B (CFB) expression as well as downregulation of complement regulatory proteins CD46, CD55, CD59, and CFH were observed in RPE cells after atRAL treatment. Furthermore, interleukin-1β production was provoked in both atRAL-treated RPE cells and microglia/macrophages. Coincubation of RPE cells with interleukin-1 receptor antagonist (IL1Ra) and atRAL ameliorated complement activation and downregulated CFB expression by attenuating both p38 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings demonstrate that atRAL induces an autocrine/paracrine IL-1/IL-1R signaling to promote complement alternative pathway activation in RPE cells and provide a novel perspective on the pathomechanism of macular degeneration.
1型斯特格黄斑变性（STGD1）和年龄相关性黄斑变性（AMD）中补体激活的潜在机制尚未完全明确。全反式视黄醛（atRAL）的过度积累被认为是这两种疾病的致病因素。通过用atRAL孵育视网膜色素上皮（RPE）细胞，我们发现C5b-9膜攻击复合物（MACs）主要通过补体替代途径产生。在atRAL处理后的RPE细胞中，观察到补体因子B（CFB）表达增加以及补体调节蛋白CD46、CD55、CD59和CFH的下调。此外，在atRAL处理的RPE细胞和小胶质细胞/巨噬细胞中均引发了白细胞介素-1β的产生。RPE细胞与白细胞介素-1受体拮抗剂（IL1Ra）和atRAL共同孵育可改善补体激活，并通过减弱p38和c-Jun氨基末端激酶（JNK）信号通路来下调CFB表达。我们的研究结果表明，atRAL诱导自分泌/旁分泌IL-1/IL-1R信号传导，以促进RPE细胞中的补体替代途径激活，并为黄斑变性的发病机制提供了新的视角。
