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: 28.05). 04/2012; 18(5):791-8. DOI: 10.1038/nm.2717
Source: PubMed

ABSTRACT 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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    • "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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    • "Thus IP can be breached not only by severe overwhelming inflammatory disease, but by chronic, low grade angiogenesis-associated inflammation as in chronic uveitis and AMD. Moreover, pathological subretinal neovascularization can be reversed by utilizing IP-promoting properties of FasL (Roychoudhury et al., 2010) and it may also be true that IL-18 produced by the RPE is a further IP-associated mediator of a constitutive anti-angiogenic response (Jiang et al., 2001; Doyle et al., 2012). Thus there is a spectrum of responses from homeostasis and health (intact IP) through aging and chronic disease (disabled IP) to fulminant (infectious) retinal necrosis (absent IP). "
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    ABSTRACT: The eye and the brain are prototypical tissues manifesting immune privilege (IP) in which immune responses to foreign antigens, particularly alloantigens are suppressed, and even completely inhibited. Explanations for this phenomenon are numerous and mostly reflect our evolving understanding of the molecular and cellular processes underpinning immunological responses generally. IP is now viewed as a property of many tissues and the level of expression of IP varies not only with the tissue but with the nature of the foreign antigen and changes in the limited conditions under which privilege can operate as a mechanism of immunological tolerance. As a result, IP functions normally as a homeostatic mechanism preserving normal function in tissues, particularly those with highly specialized function and limited capacity for renewal such as the eye and brain. However, IP is relatively easily bypassed in the face of a sufficiently strong immunological response, and the privileged tissues may be at greater risk of collateral damage because its natural defenses are more easily breached than in a fully immunocompetent tissue which rapidly rejects foreign antigen and restores integrity. This two-edged sword cuts its swathe through the eye: under most circumstances, IP mechanisms such as blood-ocular barriers, intraocular immune modulators, induction of T regulatory cells, lack of lymphatics, and other properties maintain tissue integrity; however, when these are breached, various degrees of tissue damage occur from severe tissue destruction in retinal viral infections and other forms of uveoretinal inflammation, to less severe inflammatory responses in conditions such as macular degeneration. Conversely, ocular IP and tumor-related IP can combine to permit extensive tumor growth and increased risk of metastasis thus threatening the survival of the host.
    Frontiers in Immunology 11/2012; 3:338. DOI:10.3389/fimmu.2012.00338
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    • "A separate study also reported critical roles for inflammasome-derived IL-18 in AMD. Their findings revealed that drusen droplets isolated from AMD patients incite inflammasome activation and the subsequent release of IL-1β and IL-18 (Doyle et al., 2012). However, in contrast to the other study, NLRP3 inflammasome-induced IL-18 was found to have a protective role in macular degeneration. "
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    ABSTRACT: Inflammation plays vital roles in protective responses against pathogens and tissue repair, however, improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Extensive advances have been made in recent years to define the inflammatory processes that are required for pathogen clearance, however, in comparison, less is known about the regulation of inflammation in sterile settings. Over the past decade non-communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to global human health. Thus, improved understanding of the sterile inflammatory process has emerged as one of the most important areas of biomedical investigation during our time. In this review we highlight the central role that interleukin-1 family cytokines play in sterile inflammatory diseases.
    Frontiers in Immunology 10/2012; 3:315. DOI:10.3389/fimmu.2012.00315
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