Interleukin-17 Retinotoxicity Is Prevented by Gene Transfer of a Soluble Interleukin-17 Receptor Acting as a Cytokine Blocker: Implications for Age-Related Macular Degeneration

Ardeljan, Daniel; Wang, Yujuan; Park, Stanley; Shen, Defen; Chu, Xi; Yu, Cheng‐Rong; Abu‐Asab, Mones; Tuo, Jingsheng; Eberhart, Charles G.; Olsen, Timothy W.; Mullins, Robert F.; White, Gary L.; Wadsworth, Sam; Scaria, Abraham; Chan, Chi Chao

doi:10.1371/journal.pone.0095900

Cited by 42 publications

(54 citation statements)

References 43 publications

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“…In conclusion, our results indicate that IL-17 + cells are invariably present in GA lesions but not observed in age-matched control sections confirming earlier studies of increased IL-17 staining in GA [31,32]. Our study identifies T lymphocytes as an important source of IL-17 in GA. We also showed that IBA-1 + monocytes/macrophages participate in the IL-17 production in the choroid of GA patients.…”

Section: Resultssupporting

confidence: 91%

“…Moreover, our observations suggest that T cells and monocytes/macrophages could be responsible for the significant elevation of IL-17 mRNA in maculae of eyes of AMD patients compared to control eyes [34]. It is yet unclear if and how IL-17 contributes to the pathological processes of GA. IL-17 has been shown to directly deteriorate RPE in vitro [32,35]. Moreover, IL-17 production has been associated with retinal and RPE lesions in a Nrf2-/- mice model of AMD [36] in vivo, and IL-17 could contribute to RPE degeneration in GA.…”

Section: Resultsmentioning

confidence: 99%

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Association of Choroidal Interleukin-17-Producing T Lymphocytes and Macrophages with Geographic Atrophy

et al. 2016

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Purpose: To evaluate the presence of interleukin-17 (IL-17)-producing cells in patients with geographic atrophy (GA). Methods: In this short report, we analyzed IL-17, CD3, and IBA-1 expression by immunohistochemistry on paraffin-embedded sections from 13 donors with a known history of GA, confirmed by fundus appearance and histology, and 7 age-matched control donors. Results/Conclusion: We showed that IL-17⁺ cells are found near areas of retinal pigmented epithelium atrophy in the eyes of GA patients. IL-17⁺ cells mainly localized to CD3⁺ cells, which identifies T lymphocytes, as well as IBA-1⁺ cells, which identifies mononuclear phagocytes. Therefore, IL-17 could be involved in the pathological mechanisms that contribute to the degeneration observed in GA.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Association of Choroidal Interleukin-17-Producing T Lymphocytes and Macrophages with Geographic Atrophy

et al. 2016

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“…The elevation of IL-17A expression was found not only in the peripheral blood but also in macular tissues with AMD lesions. [17][18][19] Since AMD patients usually present without systemic inflammation, we hypothesized that local IL-17A signaling was more relevant in AMD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…32 The elevated expression of IL-17RC recently was observed in chorioretinal tissues from AMD patients. 17 Therefore, the RPE cells, being resident at the chorioretinal interface, would appear a potential target of IL-17A immunologic effect. A recent report showed that IL-17A promoted ARPE-19 cells to secrete inflammatory mediators and compromised the ARPE-19 monolayer barrier function.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin-17A Induces IL-1β Secretion From RPE Cells Via the NLRP3 Inflammasome

Zhang

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Inflammasome activation and IL-1b production have been proposed to have an important role in age-related macular degeneration (AMD). Growing evidence is emerging for involvement of interleukin-17A (IL-17A) in AMD pathogenesis. We investigated the effects of IL-17A on the activation of inflammasome and production of IL-1b in primary human RPE cells. METHODS.Primary human RPE cells were isolated and cultured for the following experiments. Expression patterns of IL-17 receptor A (IL-17RA), IL-17 receptor C (IL-17RC), and ACT1 were analyzed by RT-PCR, flow cytometry, and immunofluorescence. IL-17A was added to the cell cultures, and cytokine expression, signaling pathways, and inflammasome machinery were investigated using real-time RT-PCR, ELISA, Western blot, flow cytometry, and small interfering RNA. RESULTS.Retinal pigment epithelial cells constitutively expressed IL-17RA, IL-17RC, and ACT1. IL-17A upregulated the mRNA levels of pro-IL-1b, IL-8, CCL2, and CCL20, as well as the protein level of IL-1b. IL-17A induced the phosphorylation of Akt, Erk1/2, p38 MAPK, and NFjB p65 in RPE cells. Blocking NF-jB attenuated IL-17A-induced expression of pro-IL-1b mRNA. IL-17A enhanced pro-caspase-1 and NLRP3 mRNA expression. Inhibiting caspase-1 activity and silencing NLRP3 decreased IL-1b secretion, confirming NLRP3 as the IL-17A-responsive inflammasome on the posttranscriptional level. The mechanism of IL-17A-triggered NLRP3 activation and subsequent IL-1b secretion was found to involve the generation of reactive oxygen species. CONCLUSIONS.Our results suggest that IL-17A triggers a key inflammatory mediator, IL-1b, from RPE cells, via NLRP3 inflammasome activation, holding therapeutic potential for AMD.

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Functional single nucleotide polymorphism in IL−17A 3′ untranslated region is targeted by miR‐4480 in vitro and may be associated with age‐related macular degeneration

Popp

Green

et al. 2015

Environ and Mol Mutagen

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Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly. Genetic factors contributing to AMD include single nucleotide polymorphisms (SNPs) in immune-related genes including CFH, C2, CFI, C9, and C3, thus implicating these pathways in AMD pathogenesis. MicroRNAs (miRNAs) are powerful regulators of gene expression and execute this function by binding to the 3′ untranslated region (3′UTR) of target mRNAs, leading to mRNA degradation. In this study, we searched for the possible association of SNPs in the 3′UTR region of IL-17A, a gene implicated in AMD pathogenesis without any previous SNP association with AMD. Using two independent sample cohorts of Caucasian subjects, 6 SNPs in the IL-17A 3′-UTR were selected for genotyping based on bioinformatic predictions of the SNP effect on microRNA binding. The SNP rs7747909 was found to be associated with AMD (p < 0.05) in the NEI cohort, using a dominant model logistic regression. Luciferase reporter gene assays and RNA electrophoretic mobility shift assays were performed using ARPE-19 cells to confirm the preferential binding of microRNAs to the major allele of the SNP. Our findings support the hypothesis that microRNA-mediated gene dysregulation may play a role in the pathogenesis of AMD.

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Interleukin-17 Retinotoxicity Is Prevented by Gene Transfer of a Soluble Interleukin-17 Receptor Acting as a Cytokine Blocker: Implications for Age-Related Macular Degeneration

Cited by 42 publications

References 43 publications

Association of Choroidal Interleukin-17-Producing T Lymphocytes and Macrophages with Geographic Atrophy

Association of Choroidal Interleukin-17-Producing T Lymphocytes and Macrophages with Geographic Atrophy

Interleukin-17A Induces IL-1β Secretion From RPE Cells Via the NLRP3 Inflammasome

Functional single nucleotide polymorphism in IL−17A 3′ untranslated region is targeted by miR‐4480 in vitro and may be associated with age‐related macular degeneration

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