IL‐1/IL‐1R signaling induced by all‐trans‐retinal contributes to complement alternative pathway activation in retinal pigment epithelium

• Published in: Journal of cellular physiology 2021-05, Vol.236 (5), p.3660-3674
• Main Authors: Cheng, Xinxuan, He, Danxue, Liao, Chunyan, Lin, Sijie, Tang, Liying, Wang, Yuan‐Liang, Hu, Jiaoyue, Li, Wei, Liu, Zuguo, Wu, Yalin, Liao, Yi
• Format: Article
• Language: English
• Subjects: all‐trans‐retinal; Alternative pathway; Autocrine signalling; CD46 antigen; CD59 antigen; Cell activation; Complement; Complement activation; complement alternative pathway; Complement factor B; Complement regulatory proteins; Cytokines; Epithelium; Eye diseases; Interleukin 1; Interleukin 1 receptor antagonist; interleukin‐1β; JNK protein; Kinases; Macrophages; Macular degeneration; Microglia; Paracrine signalling; Retina; Retinal pigment epithelium; Signal transduction; Signaling
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30103

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. When retinal pigment epithelium (RPE) and microglia/macrophages are challenged with all‐trans‐retinal in the subretinal space, the activation of inflammasomes promotes the secretion of mature interleukin‐1β (IL‐1β) and subsequently leads to the formation of sublytic membrane attack complexes (MACs) on the RPE surface. We hypothesize that sublytic MACs assembled on the RPE cell surface create channels to facilitate the secretion of cytokines and chemokines, such as IL‐1β, and thereby generate a self‐propagating vicious program to aggravate chronic inflammation and attract inflammatory cells in the choroid–retinal region.