Dataset Information

DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.

ABSTRACT: Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.

SUBMITTER: Tarallo V

PROVIDER: S-EPMC3351582 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.

Tarallo Valeria V Hirano Yoshio Y Gelfand Bradley D BD Dridi Sami S Kerur Nagaraj N Kim Younghee Y Cho Won Gil WG Kaneko Hiroki H Fowler Benjamin J BJ Bogdanovich Sasha S Albuquerque Romulo J C RJ Hauswirth William W WW Chiodo Vince A VA Kugel Jennifer F JF Goodrich James A JA Ponicsan Steven L SL Chaudhuri Gautam G Murphy Michael P MP Dunaief Joshua L JL Ambati Balamurali K BK Ogura Yuichiro Y Yoo Jae Wook JW Lee Dong-ki DK Provost Patrick P Hinton David R DR Núñez Gabriel G Baffi Judit Z JZ Kleinman Mark E ME Ambati Jayakrishna J

Cell 20120426 4

Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome com ...[more]

PMID: 22541070

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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.

Dataset Information

DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.

Publications

DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.

Similar Datasets

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