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.

CFH Y402H polymorphism and the complement activation product C5a: effects on NF-κB activation and inflammasome gene regulation

“…Our earlier work, and those of others, suggest that inflammasome activation is involved in the pathophysiology of AMD 10 15 16. To further support this idea, we assessed the expression of inflammasome activation products IL-1β and IL-18 in AMD eyes and compared with age-matched control eyes.…”

“…The NF-κB pathway mediates the expression of many cytokines, including classic ones such as IL-6, IL-8 and inflammasome genes 10. Therefore, we assessed the gene expression levels of NF-κB responsive genes in ARPE19 polarised cells.…”

“…The NF-κB pathway mediates the expression of classic inflammatory cytokines (interleukin (IL)-6, IL-8) and those associated with the activation of the NLRP3 inflammasomes (IL-1β, IL-18), which play important roles in AMD pathology 9 10. The relationship between C3a, C5a and NF-κB activation is unclear in the retinal pigment epithelium (RPE), a cell that is in close proximity to the choroidal circulation in outer retina.…”

pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation

“…One report showed HIF1a only provides transient protection against light induced retinal degeneration [74], while the other demonstrated this is independent on HIF1a [75]. Moreover, EPO may stimulate neovascularization in retina [76], a hallmark of age-related macular degeneration [77]. We believed CERKL, through its oxygen dependent regulation and antioxidant function, will be one of the best players in this pathway, it will be intriguing to test this in future.…”

How Research on Human Progeroid and Antigeroid Syndromes Can Contribute to the Longevity Dividend Initiative

“…Allelic variations at some 20 different genetic loci have so far been described as being pathogenetically significant for the several classifications of the disorder, which may require “multiple hits” for its full expression (Fritsche et al 2014). Since the seminal 2005 discovery of the importance of mutations at the complement factor H locus (Klein et al 2005), a number of studies have highlighted the importance of oxidative stress, inflammation and the immune system in its pathogenesis (Gao et al 2015), a view that fits with an emerging theme in geroscience referred to as “inflammaging” (Franceschi et al 2007). …”