ArticleThe Journal of biological chemistry2015
Iron-induced Local Complement Component 3 (C3) Up-regulation via Non-canonical Transforming Growth Factor (TGF)-β Signaling in the Retinal Pigment Epithelium.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 46 citations in OpenAlex.
- ASSOCIATION BETWEEN ORAL IRON SUPPLEMENTATION AND RETINAL OR SUBRETINAL HEMORRHAGE IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENT TRIALS.Retina (Philadelphia, Pa.) · 2019Trial
- Ferroptosis in retinal pigment epithelial cells: Current status and future developments.Indian journal of ophthalmology · 2026Review
- Experimental and clinical evidence of multilayer retinal damage caused by subretinal hemorrhage in neovascular age-related macular degeneration.Scientific reports · 2026Article
- Microglia-derived iron-overloaded exosomes induce neuronal ferroptosis and aggravate neurological impairment after subarachnoid hemorrhage.Journal of nanobiotechnology · 2026Article
- Transferrin is a drug candidate for the treatment of dry age-related macular degeneration (AMD).Cell death & disease · 2025Article
- Basic biology and roles of CEBPD in cardiovascular disease.Cell death discovery · 2025Review
- Cross-sectional and Longitudinal Associations Between Metal Mixtures and Serum C3, C4: Result from the Manganese‑exposed Workers Healthy Cohort.Biological trace element research · 2025Article
- Redefining cell death: ferroptosis as a game-changer in ophthalmology.Frontiers in immunology · 2025Review
- Zika virus co-opts microRNA networks to persist in placental niches detected by spatial transcriptomics.American journal of obstetrics and gynecology · 2024Article
- Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells.Disease models & mechanisms · 2023Article
- Complement and complement regulatory proteins are upregulated in lungs of COVID-19 patients.Pathology, research and practice · 2023Article
- Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction.Cell reports · 2022Article
- TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications.Biomedicines · 2022Review
- The Role of Microglia in Alzheimer's Disease From the Perspective of Immune Inflammation and Iron Metabolism.Frontiers in aging neuroscience · 2022Review
- Targeting complement components C3 and C5 for the retina: Key concepts and lingering questions.Progress in retinal and eye research · 2021Review
- Serum Iron and Ferritin Levels Are Correlated with Complement C3.Biological trace element research · 2021Article
- Iron Accumulation and Lipid Peroxidation in the Aging Retina: Implication of Ferroptosis in Age-Related Macular Degeneration.Aging and disease · 2021Review
- Ferrous but not ferric iron sulfate kills photoreceptors and induces photoreceptor-dependent RPE autofluorescence.Redox biology · 2020Article
- Review
- Increased serum proteins in non-exudative AMD retinas.Experimental eye research · 2019Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Dysregulation of iron homeostasis may be a pathogenic factor in age-related macular degeneration (AMD). Meanwhile, the formation of complement-containing deposits under the retinal pigment epithelial (RPE) cell layer is a pathognomonic feature of AMD. In this study, we investigated the molecular mechanisms by which complement component 3 (C3), a central protein in the complement cascade, is up-regulated by iron in RPE cells. Modulation of TGF-β signaling, involving ERK1/2, SMAD3, and CCAAT/enhancer-binding protein-δ, is responsible for iron-induced C3 expression. The differential effects of spatially distinct SMAD3 phosphorylation sites at the linker region and at the C terminus determined the up-regulation of C3. Pharmacologic inhibition of either ERK1/2 or SMAD3 phosphorylation decreased iron-induced C3 expression levels. Knockdown of SMAD3 blocked the iron-induced up-regulation and nuclear accumulation of CCAAT/enhancer-binding protein-δ, a transcription factor that has been shown previously to bind the basic leucine zipper 1 domain in the C3 promoter. We show herein that mutation of this domain reduced iron-induced C3 promoter activity. In vivo studies support our in vitro finding of iron-induced C3 up-regulation. Mice with a mosaic pattern of RPE-specific iron overload demonstrated co-localization of iron-induced ferritin and C3d deposits. Humans with aceruloplasminemia causing RPE iron overload had increased RPE C3d deposition. The molecular events in the iron-C3 pathway represent therapeutic targets for AMD or other diseases exacerbated by iron-induced local complement dysregulation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.