DICER1 Loss and Alu RNA Induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88

Abstract

SUMMARY 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 IL-18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL-18 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 IL-18, 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.

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

“…Numerous studies have established a role for NLRP3 inflammasome in promoting inflammation and RPE damage in response to factors associated with macular degeneration such as lysosomal destabilization (Tseng et al, 2013), oxidative stress (Kauppinen et al, 2012), and Alu RNA (Tarallo et al, 2012). The present study highlights drusen component Aβ as an important stimulus for inflammasome activation in the RPE, in keeping with similar observation of Aβ's effect in microglia (Halle et al, 2008).…”

“…More recently, the pro-inflammatory effect of Aβ 1-40 was verified in vivo using an intravitreal injection model that demonstrated upregulation of NLR family, pyrin domain containing 3 (NLRP3) inflammasome associated products (interleukin 1 beta (IL-1β), IL-18), cytokines (IL-6, tumor necrosis factor alpha (TNF-α)), and increased microglia activation (Liu et al, 2013). The NLRP3 inflammasome is an intracellular multi-protein complex that recruits and cleaves caspase-1 when activated; this inflammasome complex with activated caspase-1 in turn cleaves IL-1β and IL-18 pro-peptides into their mature forms (Halle et al, 2008;Martinon et al, 2002;Tarallo et al, 2012). A host of diverse molecules have been identified as activation signals, including pathogen-associated molecular patterns (PAMPs) such as pore-forming toxins, environmental irritants, dangerassociated molecular patterns (DAMPs) such as ATP, crystals, and proteins such as Aβ (Di Virgilio.…”

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

“…Age‐associated decline of histones or chromatin regulators known to control the heterochromatin state have been shown to contribute to the loss of heterochromatin and TE activation. More recently, DICER1 decline in aging retina has been linked to Alu retrotranspon activation and macular degeneration (Tarallo et al ., 2012). Our studies add another protein, lamin‐B, into the list of proteins whose age‐associated decline may contribute to retrotransposon activation.…”

“…Studies of the old Drosophila brains have also revealed an increased expression of several TEs, including the gypsy retrotransposon (Li et al ., 2013). More recent studies have reported increased expression of Alu retrotransposons in the retinal pigmented epithelial cells from old humans, which can contribute to age‐associated macular degeneration (Kaneko et al ., 2011; Tarallo et al ., 2012). Interestingly, increased expression of Alu retrotransposons also occur when human adult stem cells undergo senescence (Wang et al ., 2011; De Cecco et al ., 2013a), which correlates with increased formation of DNA damage foci within the TE‐enriched chromatin regions.…”

Bowman lecture on the role of inflammation in degenerative disease of the eye

“…94,95 Interestingly, a recent study has shown that isolated drusen harvested from AMD eyes have the ability to activate the inflammasome in bone marrow-derived macrophages with the release of both IL-18 and IL-1. 96 IL-18 has further been shown to promote RPE cell damage and atrophy (akin to dry AMD) 97 while there is also evidence that the IL-18 may be anti-angiogenic 96 and thus protective for wet AMD. It is intriguing to consider the possibility that the local secretion and tissue concentration of a single cytokine may determine the outcome and type of AMD and thus bear directly on visual prognosis (dry vs wet vs no AMD).…”