NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
Nature medicine (Impact Factor: 27.36). 04/2012; 18(5):791-8. DOI: 10.1038/nm.2717
Source: PubMed


Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1b (IL-1b) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress-related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD–like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3(-/-) but not Il1r1(-/-) mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD.

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Available from: Ed C Lavelle, Jan 20, 2014
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    • "Inflammasome signaling in human AMD tissues has now been observed by multiple laboratories (Chan et al., 2013; Tarallo et al., 2012; Tseng et al., 2013). Experimentally, multiple AMDrelated stimuli including Alu RNA (Kerur et al., 2013; Tseng et al., 2013), A2E (Anderson et al., 2013), complement cascade components (Doyle et al., 2012; Triantafilou et al., 2013), amyloid-b (Liu et al., 2013), and excess VEGF-A (Marneros, 2013) have been reported to act via inflammasome signaling. Our results suggest that targeting inflammasome signaling components as a ''next-generation'' therapeutic for AMD may provide additional, unanticipated benefits with respect to phenotypes arising from iron overload. "
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    ABSTRACT: Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; 11(11). DOI:10.1016/j.celrep.2015.05.023 · 8.36 Impact Factor
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    • "Likewise, it was found that the CS components localized in drusen could induce inflammasome activation, thereby potentially promoting the negative cellular effects in the affected retinas [78]. For example, Doyle et al. found that C1q could activate the NLRP3 inflammasome locally in the retinas and activate tissue macrophages [78]. These actions subsequently rupture lysosomes and release the proteolytic lysosomal content to the extracellular matrix, thereby damaging the surrounding normal cells [79]. "
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    ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.
    Research Journal of Immunology 09/2014; 2014:483960. DOI:10.1155/2014/483960
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    • "The accumulation of drusen and retinal damage in AMD is the leading cause of central vision loss in the elderly. Nlrp3 inflammasome blockade augmented retinal damage in an acute laser-induced wound-healing model (Doyle et al., 2012), but chronic NLRP3-driven IL-1b production may contribute to AMD-associated chorioretinal pathology in patients . This hypothesis is supported by studies demonstrating that deletion of Nlrp3 and caspase-1 reduced AMD pathology in two mouse models that resemble age-dependent aspects of human AMD (Marneros, 2013; Tarallo et al., 2012). "
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    ABSTRACT: Recent studies have offered a glimpse into the sophisticated mechanisms by which inflammasomes respond to danger and promote secretion of interleukin (IL)-1β and IL-18. Activation of caspases 1 and 11 in canonical and noncanonical inflammasomes, respectively, also protects against infection by triggering pyroptosis, a proinflammatory and lytic mode of cell death. The therapeutic potential of inhibiting these proinflammatory caspases in infectious and autoimmune diseases is raised by the successful deployment of anti-IL-1 therapies to control autoinflammatory diseases associated with aberrant inflammasome signaling. This Review summarizes recent insights into inflammasome biology and discusses the questions that remain in the field.
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