NLRP3 inflammasome: activation and regulation in age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly in industrialized countries. AMD is a multifactorial disease influenced by both genetic and environmental risk factors. Progression of AMD is characterized by an increase in the number and size of drusen, extracellular deposits, which accumulate between the retinal pigment epithelium (RPE) and Bruch's membrane (BM) in outer retina. The major pathways associated with its pathogenesis include oxidative stress and inflammation in the early stages of AMD. Little is known about the interactions among these mechanisms that drive the transition from early to late stages of AMD, such as geographic atrophy (GA) or choroidal neovascularization (CNV). As part of the innate immune system, inflammasome activation has been identified in RPE cells and proposed to be a causal factor for RPE dysfunction and degeneration. Here, we will first review the classic model of inflammasome activation, then discuss the potentials of AMD-related factors to activate the inflammasome in both nonocular immune cells and RPE cells, and finally introduce several novel mechanisms for regulating the inflammasome activity.

Figure 1

Clinical stages and signs of age-related macular degeneration. (a) Fundus photos demonstrate clinical features of AMD at different stages. Early AMD shows yellow extracellular drusen deposits surrounding macular area. Late AMD (GA) shows hypopigmentation or background darkening (∗) around drusen. A large number of drusen deposits are observed accumulated in the macular area. (b) Schematic diagram of drusen accumulation and RPE/photoreceptor degeneration from early to late stage AMD (GA). (c) Staining of human postmortem donor eye tissues depicting normal, early AMD, and late AMD. Arrows point to different forms of drusen: a large hard drusen in an early AMD eye and a diffuse, soft drusen in a late AMD (GA) eye. GA, geographic atrophy; ONH, optic nerve head; PR, photoreceptors; RPE, retinal pigment epithelium; BM, Bruch's membrane; CH, choroidal capillaries.

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.