Oxidative stress causes <i>Alu</i> RNA accumulation via PIWIL4 sequestration into stress granules

Hwang, Yeo Eun; Baek, Yu Mi; Baek, Ahruem; Kim, Dong-Eun

doi:10.5483/bmbrep.2019.52.3.146

Cited by 17 publications

(11 citation statements)

References 29 publications

(38 reference statements)

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“…An increase in C3aR protein expression 24 h after treatment, as shown at the mRNA level, could not be veri ed. This might be explained by storage of C3AR RNA into RNA granules, either stress granules or processing bodies (41). ARPE-19 cells express the α-chain CD11b of the integrin complement receptor CR3 (30).…”

Section: Fhr-3 Increased Endogenous Complement Activationmentioning

confidence: 99%

Complement Factor H-Related 3 induces inflammation and complosome activation in human RPE cells

Schäfer

Rasras

Ceteras

et al. 2021

Preprint

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Background Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration. The non-canonical local, cellular functions of FHR-3 remained poorly understood.Methods Human retinal pigment epithelium (RPE) cells (ARPE-19 cells and primary human RPE cells (hpRPE)), cultivated in Transwell® inserts, were apically treated with either FHR‑3 alone or with the chimerized monoclonal anti‑FHR-3 antibody RETC-2-ximab, or with FHR-1, FH, Properdin or not treated for 5 – 24 h, respectively. Interaction of FHR-3 with oxidative stress epitopes was determined by ELISA. Internalization studies of FHR-3 or FH by ARPE‑19 cells was determined by immunofluorescence live cell imaging. Impact of FHR-3 on RPE cell-specific complement components and inflammation markers were analyzed on mRNA (RT-qPCR) and on protein level (Western Blot, ELISA, protein secretion assays, immunofluorescence). Results Here, we report that FHR-3 bound to oxidative stress epitopes and competed with FH for interaction. Furthermore, FHR-3 was internalized by senescent viable RPE cells and modulated time-dependently complement component (C3, CFB) and receptor (C3aR, CR3) expression of human RPE cells. Independently of any external blood-derived proteins, complement activation products were detected. Anaphylatoxin C3a was visualized in treated cells and showed a translocation from the cytoplasm to the cell membrane after FHR-3 exposure. Subsequently, FHR-3 induced a RPE cell dependent pro-inflammatory micro-environment. Inflammasome NLRP3 activation and pro-inflammatory cytokine secretion of IL-1ß, IL-18, IL-6 and TNF-α were induced after FHR-3-RPE interaction. Additionally, important pattern recognition molecules of the innate immune system, Toll-like receptors 1 and 3, as well as proteasome subunits were impaired in RPE cells after FHR-3 incubation. A chimerized monoclonal anti-FHR-3 antibody, RETC‑2‑ximab, ameliorated the effect of FHR-3 on ARPE-19 cells.Conclusion Our studies suggest FHR-3 as an exogenous trigger molecule for the RPE cell complosome and as a productive target for a new therapeutic approach using RETC‑2‑ximab for associated degenerative diseases.

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Section: Fhr-3 Increased Endogenous Complement Activationmentioning

confidence: 99%

Complement Factor H-Related 3 induces inflammation and complosome activation in human RPE cells

Schäfer

Rasras

Ceteras

et al. 2021

Preprint

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“…Free Alu transcripts are expressed at very low levels in physiological conditions, approximately only 10 2 -10 3 molecules per cell; while the levels increases under various stresses, such as heat shock (Pandey et al, 2011), hyperglycemia (Wang et al, 2016) and viral infection (Panning and Smiley, 1994). It's been reported that Alu RNA accumulation induces ROS production and impedes SOD2 expression in cells while higher oxidative stress leads to more severe Alu RNA accumulation (Wang et al, 2016;Hwang et al, 2019). Kaneko et al (2011) found that deficiency of Dicer1, an RNase III involved in microRNA biogenesis (Bernstein et al, 2001), leads to cytotoxic Alu RNA accumulation in human RPE cells and RPE degeneration in mice shown by Fundus examination and RPE/choroid flat mount.…”

Section: Alu Rnamentioning

confidence: 99%

Not All Stressors Are Equal: Mechanism of Stressors on RPE Cell Degeneration

Tong

Wang

2020

Front. Cell Dev. Biol.

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Age-related macular degeneration (AMD) is a major cause of irreversible blindness among the elderly population. Dysfunction and degeneration of the retinal pigment epithelial (RPE) layer in the retina underscore the pathogenesis of both dry and wet AMD. Advanced age, cigarette smoke and genetic factors have been found to be the prominent risk factors for AMD, which point to an important role for oxidative stress and aging in AMD pathogenesis. However, the mechanisms whereby oxidative stress and aging lead to RPE cell degeneration are still unclear. As cell senescence and cell death are the major outcomes from oxidative stress and aging, here we review the mechanisms of RPE cell senescence and different kinds of cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, with an aim to clarify how RPE cell degeneration could occur in response to AMD-related stresses, including H 2 O 2 , 4-Hydroxynonenal (4-HNE), N-retinylidene-N-retinyl-ethanolamine (A2E), Alu RNA and amyloid β (Aβ). Besides those, sodium iodate (NaIO 3) induced RPE cell degeneration is also discussed in this review. Although NaIO 3 itself is not related to AMD, this line of study would help understand the mechanism of RPE degeneration.

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“…Alu is the most abundant transposable element, which is transcribed into Alu RNAs, and the accumulation of Alu RNAs has been confirmed to be related to AMD [76]. Alu RNAs, by reducing DICER1, can activate the inflammasome in RPE cells and increase IL-18 levels, leading to geographic atrophy.…”

Section: Abnormal Immune-inflammatory Responses Are Pathogenic Facmentioning

confidence: 99%

Autophagy Dysfunction, Cellular Senescence, and Abnormal Immune-Inflammatory Responses in AMD: From Mechanisms to Therapeutic Potential

Wang

Cheng

et al. 2019

Oxidative Medicine and Cellular Longevity

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Age-related macular degeneration (AMD) is a blinding disease caused by multiple factors and is the primary cause of vision loss in the elderly. The morbidity of AMD increases every year. Currently, there is no effective treatment option for AMD. Intravitreal injection of antivascular endothelial growth factor (anti-VEGF) is currently the most widely used therapy, but it only aims at neovascularization, which is an intermediate pathological phenomenon of wet AMD, not at the etiological treatment. Anti-VEGF therapy can only temporarily delay the degeneration process of wet AMD, and AMD is easy to relapse after drug withdrawal. Therefore, it is urgent to deepen our understanding of the pathophysiological processes underlying AMD and to identify integrated or new strategies for AMD prevention and treatment. Recent studies have found that autophagy dysfunction in retinal pigment epithelial (RPE) cells, cellular senescence, and abnormal immune-inflammatory responses play key roles in the pathogenesis of AMD. For many age-related diseases, the main focus is currently the clearing of senescent cells (SNCs) as an antiaging treatment, thereby delaying diseases. However, in AMD, there is no relevant antiaging application. This review will discuss the pathogenesis of AMD and how interactions among RPE autophagy dysfunction, cellular senescence, and abnormal immune-inflammatory responses are involved in AMD, and it will summarize the three antiaging strategies that have been developed, with the aim of providing important information for the integrated prevention and treatment of AMD and laying the ground work for the application of antiaging strategies in AMD treatment.

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Oxidative stress causes Alu RNA accumulation via PIWIL4 sequestration into stress granules

Cited by 17 publications

References 29 publications

Complement Factor H-Related 3 induces inflammation and complosome activation in human RPE cells

Complement Factor H-Related 3 induces inflammation and complosome activation in human RPE cells

Not All Stressors Are Equal: Mechanism of Stressors on RPE Cell Degeneration

Autophagy Dysfunction, Cellular Senescence, and Abnormal Immune-Inflammatory Responses in AMD: From Mechanisms to Therapeutic Potential

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