NLRP3 Inflammasome Activation in Retinal Pigment Epithelial Cells by Lysosomal Destabilization: Implications for Age-Related Macular Degeneration

Tseng, Wen Allen; Thein, Thuzar; Kinnunen, Kati; Lashkari, Kameran; Gregory, Meredith S.; D'Amore, Patricia A.; Ksander, Bruce R.

doi:10.1167/iovs.12-10655

Cited by 239 publications

(319 citation statements)

References 54 publications

(80 reference statements)

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“…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).…”

Section: Discussionsupporting

confidence: 88%

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

Liu

Wang

et al. 2014

Experimental Eye Research

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Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κB. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Aβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use.

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Section: Discussionsupporting

confidence: 88%

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

Liu

Wang

et al. 2014

Experimental Eye Research

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“…Combined data from three experiments are shown as mean ± SEM. ** denotes P < 0.01 and *** P < 0.001, Mann-Whitney U-test retinal pigment epithelial (RPE) cells (Tseng et al 2013), and it seems to act similarly also in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal destabilization activates the NLRP3 inflammasome in human umbilical vein endothelial cells (HUVECs)

Kinnunen

Piippo

Loukovaara

et al. 2017

J. Cell Commun. Signal.

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Inflammation is a crucial component in the pathogenesis of many vascular diseases, such as atherosclerosis and diabetes. Inflammasomes are intracellular signalling complexes whose activation promotes inflammation. Nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) is a pattern recognition receptor (PRR) forming the best-known inflammasome. Disturbances in NLRP3 have been associated with multiple diseases. The purpose of this study was to explore the lysosomal destabilizationrelated NLRP3 inflammasome signaling pathway in human endothelial cells. In order to prime and activate NLRP3, human umbilical vein cells (HUVECs) were exposed to TNF-α and the lysosomal destructive agent Leusine-Leusine-OMethylesther (Leu-Leu-OMe), respectively. A caspase-1 inhibitor was used to block caspase-1's enzymatic function and an interleukin 1 receptor antagonist (IL-1RA) to prevent any possible secondary effects of IL-1β. Leu-Leu-OMe increased the expression of NLRP3, IL-1β, and IL-18 in HUVECs. Exposure to Leu-Leu-OMe significantly promoted the production of IL-6 and IL-8 in primed HUVECs; this effect was prevented by the pre-treatment of cells with an IL-1RA. Our results suggest that lysosomal destabilization activates the NLRP3 inflammasome pathway that promotes the production of IL-6 and IL-8 in an autocrine manner in HUVEC cells.

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“…The inflammasome is a multiprotein complex comprising a sensor protein, the adaptor protein ASC (apoptosisassociated speck-like domain containing caspase recruitment domain), and the inflammatory protease caspase-1. The eye has many inflammasome-forming sensors 49 including NLRP receptor molecules (nucleotidebinding domain and leucine-rich repeat containing pyrin domain family). Inflammasome-dependent biological effects may be mediated not only by IL-1b and IL-18, but also by the multifaceted activities of caspase-1.…”

Section: Understanding Uveitismentioning

confidence: 99%

Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses.

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NLRP3 Inflammasome Activation in Retinal Pigment Epithelial Cells by Lysosomal Destabilization: Implications for Age-Related Macular Degeneration

Cited by 239 publications

References 54 publications

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

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

Lysosomal destabilization activates the NLRP3 inflammasome in human umbilical vein endothelial cells (HUVECs)

Doyne lecture 2016: intraocular health and the many faces of inflammation

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