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NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration.

ABSTRACT: The NLRP3 inflammasome is activated in age-related macular degeneration (AMD), but it remains unknown whether its activation contributes to AMD pathologies. VEGF-A is increased in neovascular ("wet") AMD, but it is not known whether it plays a role in inflammasome activation, whether an increase of VEGF-A by itself is sufficient to cause neovascular AMD and whether it can contribute to nonexudative ("dry") AMD that often co-occurs with the neovascular form. Here, it is shown that an increase in VEGF-A results in NLRP3 inflammasome activation and is sufficient to cause both forms of AMD pathologies. Targeting NLRP3 or the inflammasome effector cytokine IL-1? inhibits but does not prevent VEGF-A-induced AMD pathologies, whereas targeting IL-18 promotes AMD. Thus, increased VEGF-A provides a unifying pathomechanism for both forms of AMD; combining therapeutic inhibition of both VEGF-A and IL-1? or the NLRP3 inflammasome is therefore likely to suppress both forms of AMD.

SUBMITTER: Marneros AG

PROVIDER: S-EPMC3821550 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration.

Marneros Alexander G AG

Cell reports 20130905 5

The NLRP3 inflammasome is activated in age-related macular degeneration (AMD), but it remains unknown whether its activation contributes to AMD pathologies. VEGF-A is increased in neovascular ("wet") AMD, but it is not known whether it plays a role in inflammasome activation, whether an increase of VEGF-A by itself is sufficient to cause neovascular AMD and whether it can contribute to nonexudative ("dry") AMD that often co-occurs with the neovascular form. Here, it is shown that an increase in ...[more]

PMID: 24012762

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Project description:PurposeAge-related macular degeneration (AMD) can result in severe vision loss and blurriness in the older population. The early and intermediate stages of AMD typically start without noticeable symptoms and can only be detected with a comprehensive eye exam. Because of the quiet onset of the disease, it is necessary to identify potential biomarkers to aid in the diagnosis, staging, and association with disease onset. Inflammasome signaling proteins are prominent biomarkers in the central nervous system, and the inflammasome has been shown to play a role in the innate inflammatory response in aging and AMD.MethodsSerum from healthy controls and AMD patients were analyzed for the protein levels of Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18 and C-reactive protein (CRP) to determine cutoff points, positive and negative predictive values, and receiver operator characteristic curves, as well as univariate and multivariate linear and logistic regression models.ResultsASC, IL-18, and CRP were elevated in the serum of AMD patients when compared to healthy controls. The area under the curve (AUC) for ASC was 0.98 with a cutoff point of 365.6 pg/mL, whereas IL-18 had an AUC of 0.73 and a cutoff point of 242.4 pg/mL, and the AUC for CRP was 0.67 with a cutoff point of 8,684,152 pg/mL. Levels of IL-18 had a statistically significant linear correlation with that of ASC with an adjusted R 2 of 0.1906, indicating that 19% of IL-18 could be explained by ASC protein levels in serum. Moreover, a logistic regression model for the diagnosis of AMD consists of ASC and having a diagnosis of hypertension, indicating that these two factors (elevated levels of ASC and a diagnosis of hypertension [HTN]) are associated with the diagnosis of AMD.ConclusionsASC, IL-18, and CRP are elevated in patients with AMD, and the protein levels of IL-18 are partially the result of ASC protein expression. Moreover, elevated protein levels of ASC in serum and a diagnosis of HTN increase the odds of patients having a diagnosis of AMD.Translational relevanceBiomarkers of AMD may be used to monitor disease risk, response to treatment and disease progression.

Project description:UnlabelledAge-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p<0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression.Trial registrationThe Netherlands National Trial Register NTR2605.

Dataset Information

NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration.

Publications

NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration.

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