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Complement factor H binds malondialdehyde epitopes and protects from oxidative stress
Open accessAbstract
Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.
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“Oxidative stress adducts and components of the complement system have been found to accumulate in drusen and sub-RPE deposits of patients with AMD (Weismann et al., 2011; Shaw et al., 2012), and mice with mutations making them prone to oxidative stress or dysregulation of the complement pathway have been presented as models of AMD (Imamura et al., 2006; Justilien et al., 2007; Hollyfield et al., 2”
From Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis (2015) · cites this paper as Weismann et al., 2011
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Cites
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Esterbauer, H., Schaur, R. J., & Zollner, H. (1991) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(91)90192-6 · Cited by 6,672
Complement factor H polymorphism in age-related macular degeneration
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J.-Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., et al. (2005) · Science · doi:10.1126/science.1109557 · Cited by 4,492
Complement factor H polymorphism and age-related macular degeneration
Edwards, A. O., Ritter, R., Abel, K. J., Manning, A., Panhuysen, C., & Farrer, L. A. (2005) · Science · doi:10.1126/science.1110189 · Cited by 2,449
Complement factor H variant increases the risk of age-related macular degeneration
Haines, J. L., Hauser, M. A., Schmidt, S., Scott, W. K., Olson, L. M., Gallins, P., Spencer, K. L., Kwan, S. Y., Noureddine, M., Gilbert, J. R., et al. (2005) · Science · doi:10.1126/science.1110359 · Cited by 2,424
Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501536102 · Cited by 1,961
A blast from the past: clearance of apoptotic cells regulates immune responses
Savill, J., Dransfield, I., Gregory, C. D., & Haslett, C. (2002) · Nature reviews. Immunology · doi:10.1038/nri957 · Cited by 1,574
Age-related macular degeneration
Jager, R. D., Mieler, W. F., & Miller, J. W. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0801537 · Cited by 1,379
Complement regulators and inhibitory proteins
Zipfel, P. F., & Skerka, C. (2009) · Nature reviews. Immunology · doi:10.1038/nri2620 · Cited by 1,268
Age-related macular degeneration
de Jong, P. T. V. M. (2006) · New England Journal of Medicine · doi:10.1056/nejmra062326 · Cited by 787
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Cited by
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Ayala, A., Muñoz, M., & Argüelles, S. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/360438 · Cited by 6,837
“adducts with FH can block both the uptake ofMDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice [184]; MDA adducts or MAA adducts can promote binding of complement; (iii) anaphylatoxin C3a (proinflammatory complement components) with oxidatively modified low-density lipoprotein…”
BackgroundComplement System Part I – Molecular Mechanisms of Activation and Regulation
Merle, N. S., Church, S. E., Fremeaux-Bacchi, V., & Roumenina, L. T. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00262 · Cited by 1,620
“Y402H binds more weakly to MDA and oxidized phospholipids expressed on retinal pigment epithelium compared to the non-mutated protein (198, 200).”
BackgroundComplement System Part II: Role in Immunity
Merle, N. S., Noé, R., Halbwachs‐Mecarelli, L., Frémeaux‐Bacchi, V., & Roumenina, L. T. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00257 · Cited by 1,113
“At risk, FH variant H402 has a weaker capacity to interact with oxidized lipids and malondialdehyde in the drusen, thus allowing constant background complement activation, leading to retinal epithelial cells damage and macrophages activation (249, 250).”
BackgroundBhutto, I. A., & Lutty, G. A. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.04.005 · Cited by 1,028
“Weismann and associates have demonstrated that CFH binds malondialdehyde epitopes and protects against oxidative stress (Weismann et al., 2011).”
BackgroundAge-related macular degeneration
Fleckenstein, M., Keenan, T. D. L., Guymer, R. H., Chakravarthy, U., Schmitz-Valckenberg, S., Klaver, C. C. W., Wong, W. T., & Chew, E. Y. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00265-2 · Cited by 1,093
Metadata
- Authors
- Weismann, D., Hartvigsen, K., Lauer, N., Bennett, K. L., Scholl, H. P. N., Issa, P. C., Cano, M., Brandstätter, H., Tsimikas, S., Skerka, C., Superti-Furga, G., Handa, J. T., Zipfel, P. F., Witztum, J. L., & Binder, C. J.
- Affiliations
- Austrian Academy of Sciences (AT)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Johns Hopkins University (US)
- University of Oxford (GB)
- Octapharma (Austria) (AT)
- University of California San Diego (US)
- Corresponding author
- Binder, Christoph J.
- ORCID
- Venue
- Nature
- Published
- 2011-10
- Volume
- 478
- Issue
- 7367
- Pages
- 76-81
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4826616
- OpenAlex
- W2062097745
- Cited by
- 533
- References
- 42
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 25 · 2023: 30 · 2022: 29 · 2021: 42 · 2020: 36 · 2019: 29 · 2018: 33 · 2017: 31 · 2016: 39 · 2015: 42 · 2014: 44 · 2013: 66 · 2012: 44
- FWCI
- 22.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01-HL086599, HL-088093, P01HL088093)
- National Eye Institute (EY14005, R01EY014005, EY019044, R01EY019904)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- complement factor H, malondialdehyde, lipid peroxidation, oxidative stress, age-related macular degeneration, macrophage uptake, pro-inflammatory effects, innate immunity, chronic inflammation, retina
- MeSH terms
- Animals, Epitopes, Binding Sites, Complement System Proteins, Complement Inactivator Proteins, Enzyme-Linked Immunosorbent Assay, Female, Humans, Inflammation, Macular Degeneration, Male, Malondialdehyde, Mice, Inbred C57BL, Mutation, Necrosis, Protein Binding, Retina, Lipid Peroxidation, Apoptosis, Complement Factor H, Protein Structure, Tertiary, Macrophages, Peritoneal, Oxidative Stress, Mice
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