Review Article

NLRP3 Inflammasome: Activation and Regulation in Age-Related Macular Degeneration

Figure 2

Current model of NLRP3 inflammasome activation in RPE. (1) Priming of the RPE by one of the following factors (LPS [17], TNF-α [17], IL-1α [17], CEP [18], and Aβ1-40 [19]) is needed in order to activate the NF-κB pathway, which can be specifically blocked by vinpocetine or BAY 11-7082 [19]. Intriguingly, DICER1 deficiency induced Alu RNA accumulation has also been demonstrated to prime NF-κB signaling, independent of toll-like receptors (TLRs) [20]. (2) Once the NF-κB pathway is active, it promotes the transcription of NLRP3 and pro-IL-1β. (3–7) For the production of mature IL-1β and IL-18; separate inflammasome components are assembled as a multiprotein complex triggered by one of the following mechanisms: K+ efflux via P2X7 receptor activation in response to extracellular ATP accumulation or intracellular Alu RNA [20] (3); cytoplasmic cathepsin B release from destabilized phagolysosomes of lipofuscin/A2E [21] (4); ROS overproduction caused by 4-HNE [22] (5). Other NLRP3 inflammasome activation mechanisms that have been reported in immune cells but not validated in RPE cells are shown in red text and arrows. These include drusen components (C1q [18] and fibrillar Aβ [23]) induced lysosomal damage (4), C3a triggered ATP efflux [24], MAC formation [25] (6), BRCC3-mediated deubiquitylation [26], and LUBAC-mediated ubiquitylation [27] (7). (8) Successful assembly of NLRP3 inflammasome triggers autoproteolysis of procaspase-1 into active caspase-1, which further oligomerizes to convert pro-IL-1β and pro-IL-18 into bioactive peptides. (9) The biological significance of NLRP3 inflammasome activation is to release active IL-1β and IL-18 into extracellular space through exocytosis. The secreted IL-1β will facilitate inflammation process in the tissue whereas IL-18 will either promote caspase-3 dependent RPE apoptosis via MyD88 signaling or suppress neovascular vessels growth in the choroid capillaries.