Hypoxic expression of NLRP3 and VEGF in cultured retinal pigment epithelial cells: contribution of P2Y2 receptor signaling

Doktor, Fabian; Prager, Philipp; Wiedemann, Peter; Kohen, Leon; Bringmann, Andreas; Hollborn, Margrit

doi:10.1007/s11302-018-9631-6

Cited by 20 publications

(14 citation statements)

References 49 publications

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“…Of those, especially inflammasome signaling and the mtDNA-mediated cGAS/STING pathway, activation have been implicated in RPE cells as mitochondria-related mediators of inflammation. mtDNA-driven NF-κB or MAPK activation, as well as ATP-regulated P 2 Y 1 receptor signaling are also able to implement the priming signal for the inflammasome activation in RPE cells ( Prager et al, 2016 ; Doktor et al, 2018 ; Fann et al, 2018 ). NF-κB p65 activity may be a critical upstream initiator of p62/SQSTM1 expression in RPE cells under oxidative stress that links inflammatory signaling to autophagy and NFE2L2 cascades ( Song et al, 2017 ).…”

Section: Mitochondrial Dysfunction In the Induction Of Inflammationmentioning

confidence: 99%

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Kaarniranta

Uusitalo

Błasiak

et al. 2020

Progress in Retinal and Eye Research

324

284

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Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is considered to be a key factor in age-related macular degeneration (AMD) pathology. RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in RPE as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of RPE degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent RPE cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in RPE degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

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Section: Mitochondrial Dysfunction In the Induction Of Inflammationmentioning

confidence: 99%

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Kaarniranta

Uusitalo

Błasiak

et al. 2020

Progress in Retinal and Eye Research

324

284

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“…Chronic intermittent hypoxia increased levels of cytokines associated with M1-and M2-like microglial activation states ( Snyder et al, 2017 ). In retinal pigmented epithelial cells, hypoxia induced expression of NLRP3 and IL-1β in a pathway dependent upon ATP release and the P2Y12 receptor, and inflammasome activation killed cells only under hypoxic conditions ( Doktor et al, 2018 ). HIF-1α is implicated in hypoxia-mediated inflammasome priming as blockage of HIF-1α reduced expression of NLRP3, caspase 1 and IL-1β and of pyroptotic death in a stroke model ( Jiang et al, 2020 ).…”

Section: Hypoxia Contributes To Inflammationmentioning

confidence: 99%

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

2021

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Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial and inflammatory signaling can exacerbate issues in chronic neurodegenerations. This review discusses evidence for the interaction between mitochondrial damage and inflammation, with a focus on glaucomatous neurodegeneration, and proposes that positive feedback resulting from this crosstalk drives pathology. Mitochondrial dysfunction exacerbates inflammatory signaling in multiple ways. Damaged mitochondrial DNA is a damage-associated molecular pattern, which activates the NLRP3 inflammasome; priming and activation of the NLRP3 inflammasome, and the resulting liberation of IL-1β and IL-18 via the gasdermin D pore, is a major pathway to enhance inflammatory responses. The rise in reactive oxygen species induced by mitochondrial damage also activates inflammatory pathways, while blockage of Complex enzymes is sufficient to increase inflammatory signaling. Impaired mitophagy contributes to inflammation as the inability to turnover mitochondria in a timely manner increases levels of ROS and damaged mtDNA, with the latter likely to stimulate the cGAS-STING pathway to increase interferon signaling. Mitochondrial associated ER membrane contacts and the mitochondria-associated adaptor molecule MAVS can activate NLRP3 inflammasome signaling. In addition to dysfunctional mitochondria increasing inflammation, the corollary also occurs, with inflammation reducing mitochondrial function and ATP production; the resulting downward spiral accelerates degeneration. Evidence from several preclinical models including the DBA/2J mouse, microbead injection and transient elevation of IOP, in addition to patient data, implicates both mitochondrial damage and inflammation in glaucomatous neurodegeneration. The pressure-dependent hypoxia and the resulting metabolic vulnerability is associated with mitochondrial damage and IL-1β release. Links between mitochondrial dysfunction and inflammation can occur in retinal ganglion cells, microglia cells and astrocytes. In summary, crosstalk between damaged mitochondria and increased inflammatory signaling enhances pathology in glaucomatous neurodegeneration, with implications for other complex age-dependent neurodegenerations like Alzheimer’s and Parkinson’s disease.

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“…), P2X7R, and VEGF-A and enhanced the production of ROS [17]. The hypoxic NLRP3 and VEGF gene expression and the secretion of VEGF are in part 15 Oxidative Medicine and Cellular Longevity mediated by purinergic receptor signaling [35]. NF-κB and P2X7R are critical signaling intermediates in Alu RNAinduced inflammasome priming and RPE degeneration.…”

Section: Discussionmentioning

confidence: 99%

P2X7 Receptor Antagonist Attenuates Retinal Inflammation and Neovascularization Induced by Oxidized Low‐Density Lipoprotein

Yang

Qiu

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Age-related macular degeneration (AMD) is a common and severe blinding disease among people worldwide. Retinal inflammation and neovascularization are two fundamental pathological processes in AMD. Recent studies showed that P2X7 receptor was closely involved in the inflammatory response. Here, we aim to investigate whether A740003, a P2X7 receptor antagonist, could prevent retinal inflammation and neovascularization induced by oxidized low-density lipoprotein (ox-LDL) and explore the underlying mechanisms. ARPE-19 cells and C57BL/6 mice were treated with ox-LDL and A740003 successively for in vitro and in vivo studies. In this research, we found that A740003 suppressed reactive oxygen species (ROS) generation and inhibited the activation of Nod-like receptor pyrin-domain protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathway. A740003 also inhibited the generation of angiogenic factors in ARPE-19 cells and angiogenesis in mice. The inflammatory cytokines and phosphorylation of inhibitor of nuclear factor-κB alpha (IKBα) were repressed by A740003. Besides, ERG assessment showed that retinal functions were remarkably preserved in A740003-treated mice. In summary, our results revealed that the P2X7 receptor antagonist reduced retinal inflammation and neovascularization and protected retinal function. The protective effects were associated with regulation of NLRP3 inflammasome and the NF-κB pathway, as well as inhibition of angiogenic factors.

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Hypoxic expression of NLRP3 and VEGF in cultured retinal pigment epithelial cells: contribution of P2Y2 receptor signaling

Cited by 20 publications

References 49 publications

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

P2X7 Receptor Antagonist Attenuates Retinal Inflammation and Neovascularization Induced by Oxidized Low‐Density Lipoprotein

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