Fig. 3

NLRP3 activation via P2 × 7 signalling within RPE and macrophages. A schematic depicting the cell signalling pathways that leads to RPE degeneration or pyroptosis. In either immune cell (e.g., macrophage) or RPE, multiple stimuli such as Alu RNA, ROS or extracellular ATP can stimulate NLRP3 inflammasome. In canonical stimulation leading to RPE degeneration, NLRP3 is activated and, co-activates the P2 × 7 receptor. Alu RNA causes upregulation of interferon type 1 and NF-κB regulated cytokines (e.g. pro-IL-18). Assembly of the NLRP3 following either ATP, Alu RNA or ROS stimulation allows for processing of pro-interleukins into mature IL-1β and IL-18. Microvesicles can release IL-1β to stimulate inflammatory responses further. IL-18 binds to IL-18 receptor to induce RPE degeneration via MyD88 signalling. In non-canonical stimulation, RPE degeneration occurs due to Alu RNA stimulation of GSDMD via cGAS-STING signalling. The activation of GSDMD results in GSDMD pore formation that causes pyroptosis cell death in RPE cells and secondary activation of the NLRP3 inflammasome. Black arrows indicate a known signalling step. Dashed arrow steps indicate postulated signalling step