Cited by 533Complement system in diseasesRetinal Diseases and TreatmentsAntioxidant Activity and Oxidative Stress

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Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

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Weismann, David, Hartvigsen, Karsten, Lauer, Nadine, Bennett, Keiryn L., Scholl, Hendrik P. N., Issa, Peter Charbel, Cano, Marisol, Brandstätter, Hubert, Tsimikas, Sotirios, Skerka, Christine, Superti-Furga, Giulio, Handa, James T., Zipfel, Peter F., Witztum, Joseph L., Binder, Christoph J.·2011·Nature

DOI 10.1038/nature10449PMC PMC4826616

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Abstract

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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Different Therapeutic Approaches for Dry and Wet AMD
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“CFH plays a key role in the regulation of complement activation and represents a defense against lipid peroxidation and oxidative stress [22–25].”
Oxidative Stress and Neurobiology of Demyelination
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“The probable mechanism in the basis of this effect is the takeover of molecules modified by MDA activity by phagocytic cells, which prevents the loss of immunotolerance and, in that way, the adverse effects in the nervous tissue which could be initiated [107].”
Background
Of mice and men: The factor H protein family and complement regulation
Pouw, R. B., Vredevoogd, D. W., Kuijpers, T. W., & Wouters, D. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.03.011 · Cited by 61
Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family
Sánchez‐Corral, P., Pouw, R. B., López‐Trascasa, M., & Józsi, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01607 · Cited by 58
“FH was shown to bind to MDA/ MAA epitopes and inhibit complement activation and the proinflammatory effects of such MDA/MAA epitopes (99).”
Background
CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex
Borras, C., Canonica, J., Jorieux, S., Abache, T., Sanharawi, M. E., Klein, C., Delaunay, K., Jonet, L., Salvodelli, M., Naud, M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-50420-9 · Cited by 58
Risk Alleles in CFH and ARMS2 and the Long-term Natural History of Age-Related Macular Degeneration
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“The CFH gene also affects the metabolism of lipids, such as malondialdehyde, thataccumulate inresponse tooxidative stressandare thought tocontribute toRPEcelldeath.(67) The role of ARMS2 is also uncertain.”
Complement dysregulation in AMD: RPE-Bruch’s membrane-choroid
Sparrow, J. R., Ueda, K., & Zhou, J. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.03.007 · Cited by 59
“Interestingly, the 402H polymorphism also reduced the ability of CFH to bind MDA.”
BackgroundInfluential
PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis
Senders, M. L., Que, X., Cho, Y. S., Yeang, C., Groenen, H., Fay, F., Calcagno, C., Meerwaldt, A. E., Green, S., Miu, P., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.11.036 · Cited by 58
Evolution of oxidative stress, inflammation and neovascularization in the choroid and retina in a subretinal lipid induced age-related macular degeneration model
Kim, S., Kambhampati, S. P., Bhutto, I. A., McLeod, D. S., Lutty, G. A., & Kannan, R. M. (2020) · Experimental Eye Research · doi:10.1016/j.exer.2020.108391 · Cited by 60
Candida and Complement: New Aspects in an Old Battle
Harpf, V., Rambach, G., Würzner, R., Lass‐Flörl, C., & Speth, C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01471 · Cited by 55
Remodeling liver microenvironment by L-arginine loaded hollow polydopamine nanoparticles for liver cirrhosis treatment
Wang, Y., Liu, Y., Liu, Y., Zhong, J., Wang, J., Sun, L., Yu, L., Wang, Y., Li, Q., Jin, W., et al. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122028 · Cited by 56
Oxidative stress in dry age-related macular degeneration and exfoliation syndrome
Chiras, D., Kitsos, G., Petersen, M. B., Skalidakis, I., & Κroupis, C. (2014) · Critical Reviews in Clinical Laboratory Sciences · doi:10.3109/10408363.2014.968703 · Cited by 56
Proteomic Landscape of the Human Choroid–Retinal Pigment Epithelial Complex
Skeie, J. M., & Mahajan, V. B. (2014) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2014.2065 · Cited by 56
Phospholipase A 2 Enzymes, High-Dose Atorvastatin, and Prediction of Ischemic Events After Acute Coronary Syndromes
Ryu, S. K., Mallat, Z., Bénessiano, J., Tedgui, A., OLSSON, A. G., Bao, W., Schwartz, G. G., Tsimikas, S., & for the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) Trial Investigators (2012) · Circulation · doi:10.1161/circulationaha.111.063487 · Cited by 56
Interlink between Inflammation and Oxidative Stress in Age-Related Macular Degeneration: Role of Complement Factor H
Romero‐Vázquez, S., Llorens, V., Soler-Boronat, A., Figueras‐Roca, M., Adán, A., & Molins, B. (2021) · Biomedicines · doi:10.3390/biomedicines9070763 · Cited by 56
“Indeed, MDA can cause RPE damage and MDA-modified proteins are known to induce inflammatory responses and are recognized by innate immunity [51,52].”
BackgroundInfluential
The Complement Inhibitor Factor H Generates an Anti-Inflammatory and Tolerogenic State in Monocyte-Derived Dendritic Cells
Olivar, R., Luque, A., Cárdenas-Brito, S., Naranjo‐Gómez, M., Blom, A. M., Borràs, F. E., de Córdoba, S. R., Zipfel, P. F., & Aran, J. M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1500455 · Cited by 55
“inflammation (14), protection from oxidative stress (15), modulation of platelet structure and function (16), anticoagulation (17), and regulation of cellular immune-inflammatory responses by in-”
Background
CERKL interacts with mitochondrial TRX2 and protects retinal cells from oxidative stress-induced apoptosis
Li, C., Wang, L., Zhang, J., Huang, M. N., Wong, F., Liu, X., Liu, F., Cui, X., Yang, G., Chen, J., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.009 · Cited by 53
Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine
Gonen, A., Hansen, L. F., Turner, W. W., Montano, E. N., Que, X., Rafia, A., Chou, M.-Y., Wiesner, P., Tsiantoulas, D., Corr, M., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m053256 · Cited by 53
Tetrastigma hemsleyanum tubers polysaccharide ameliorates LPS-induced inflammation in macrophages and Caenorhabditis elegans
Chu, Q., Jia, R., Chen, M., Li, Y., Yu, X., Wang, Y., Chen, W., Ye, X., Liu, Y., Jiang, Y., et al. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.09.039 · Cited by 53
Alternative Complement Pathway Deficiency Ameliorates Chronic Smoke-Induced Functional and Morphological Ocular Injury
Woodell, A. S., Coughlin, B. A., Kunchithapautham, K., Casey, S. E., Williamson, T., Ferrell, W. D., Atkinson, C., Jones, B. W., & Rohrer, B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067894 · Cited by 52
“Likewise, the Y402H allele, which binds less effectively to malondialdehyde epitopes and oxidized phospholipids (generated by oxidative stress [92,93]), is correlated with the size of peripheral drusen and increases in reticular pigment [14,15].”
Background
Induction of Tolerogenic Dendritic Cells by Endogenous Biomolecules: An Update
Švajger, U., & Rožman, P. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02482 · Cited by 52
“Besides the direct negative regulation of complement activation, FH also interacts with other endogenous ligands or receptors which extends its activity to protection from oxidative stress (99), modulation of platelet function (100), and regulation of immunity via interaction with several cells of the immune system (1…”
Background
Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis
Segers, F. M., Verdam, F. J., de Jonge, C., Boonen, B., Driessen, A., Shiri-Sverdlov, R., Bouvy, N. D., Greve, J. W. M., Buurman, W. A., & Rensen, S. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110053 · Cited by 50
“Low factor H expression may also play a role in the detrimental effects of lipid peroxidation products in NASH [12,23], since factor H was recently shown to recognize epitopes associated with oxidative stress and to mediate their neutralization [24].”
Background
The hijackers guide to escaping complement: Lessons learned from pathogens
Ermert, D., Ram, S., & Laabei, M. (2019) · Molecular Immunology · doi:10.1016/j.molimm.2019.07.018 · Cited by 51
Canonical and non-canonical roles of complement in atherosclerosis
Maffia, P., Mauro, C., Case, A. G., & Kemper, C. (2024) · Nature Reviews Cardiology · doi:10.1038/s41569-024-01016-y · Cited by 53
“The classical pathway is initiated by binding of the C1q subunit within the C1 complex to immune complexes or DAMPs exposed by stressed or dying cells, which then induces the activation of C4 and C2 into C4a and C4b and C2a and C2b, respectively.”
Influential
Interrelation Between Oxidative Stress and Complement Activation in Models of Age-Related Macular Degeneration
Pujol-Lereis, L. M., Schäfer, N., Kuhn, L. B., Rohrer, B., & Pauly, D. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-17121-0_13 · Cited by 49
Daily zeaxanthin supplementation prevents atrophy of the retinal pigment epithelium (RPE) in a mouse model of mitochondrial oxidative stress
Biswal, M. R., Justis, B. D., Han, P., Li, H., Gierhart, D. L., Dorey, C. K., & Lewin, A. S. (2018) · PLoS ONE · doi:10.1371/journal.pone.0203816 · Cited by 50
Relationship between the complement system, risk factors and prediction models in age-related macular degeneration
Bora, N. S., Matta, B., Lyzogubov, V. V., & Bora, P. S. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2014.07.012 · Cited by 49
Manipulating the mediator: Modulation of the alternative complement pathway C3 convertase in health, disease and therapy
Ricklin, D. (2012) · Immunobiology · doi:10.1016/j.imbio.2012.07.016 · Cited by 49
Suppression of Light-Induced Oxidative Stress in the Retina by Mitochondria-Targeted Antioxidant
Baksheeva, V. E., Tiulina, V. V., Tikhomirova, N. K., Gancharova, O. S., Komarov, S. V., Philippov, P. P., Zamyatnin, A. A., Senin, I. I., & Zernii, E. Y. (2018) · Antioxidants · doi:10.3390/antiox8010003 · Cited by 47
“First, the illuminated retina exhibited increased lipid peroxidation manifesting in elevation of MDA content (Figure 2).”
BackgroundInfluential
Effects of substance use disorder on oxidative and antioxidative stress markers: A systematic review and meta‐analysis
Viola, T. W., Orso, R., Florian, L. F., Garcia, M. G., Gomes, M. G. S., Mardini, E. M., Niederauer, J. P. O., Zaparte, A., & Grassi‐Oliveira, R. (2022) · Addiction Biology · doi:10.1111/adb.13254 · Cited by 50
Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration
Clark, S. J., & Bishop, P. (2014) · Journal of Clinical Medicine · doi:10.3390/jcm4010018 · Cited by 46
“Age-dependent changes in the levels of metal ions [47] and products of oxidative stress [48,49] have been suggested as possible contributors to this phenomenon.”
Background
High-density lipoproteins are a potential therapeutic target for age-related macular degeneration
Kelly, U., Grigsby, D., Cady, M. A., Landowski, M., Skiba, N. P., Liu, J., Remaley, A. T., Klingeborn, M., & Rickman, C. B. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.012305 · Cited by 46
“The Y402H polymorphism decreases the binding of FH to heparin (22,26), M6 protein of Streptococcus pyogenes (26,27), CRP (22,26-28), Bruch’s membrane (BrM) (29), malondialdehyde (MDA) epitopes (30) and oxidized phospholipids (31).”
Background
Circulating glutathione peroxidase and superoxide dismutase levels in patients with epilepsy: A meta-analysis
Wang, M., Zhang, X., Jia, W., Zhang, C., Boczek, T., Harding, M. H., Liu, Y., Li, M., Zhang, S., Lei, S., et al. (2021) · Seizure · doi:10.1016/j.seizure.2021.07.001 · Cited by 46
Effects of pitavastatin and atorvastatin on lipoprotein oxidation biomarkers in patients with dyslipidemia
Yoshida, H., Shoda, T., Yanai, H., Ikewaki, K., Kurata, H., Ito, K., Furutani, N., Tada, N., Witztum, J. L., & Tsimikas, S. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.10.069 · Cited by 46
Plasma levels of complement proteins from the alternative pathway in patients with age-related macular degeneration are independent of Complement Factor H Tyr⁴⁰²His polymorphism.
Silva, A. S., Teixeira, A., Bavia, L., Lin, F. L. H., Velletri, R., Belfort, R., & Isaac, L. (2012) · Europe PMC (PubMed Central) · Cited by 46
Thioredoxin rod-derived cone viability factor protects against photooxidative retinal damage
Elachouri, G., Lee-Rivera, I., Clérin, E., Argentini, M., Fridlich, R., Blond, F., Ferracane, V., Yang, Y., Raffelsberger, W., Wan, J., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.01.003 · Cited by 46
Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration
Hammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44
“A lack of functional FH may also impair the clearance of lipid peroxidation products [131], leading to oxidative stress [139].”
Background
The complement system: a novel therapeutic target for age-related macular degeneration
Shughoury, A., Sevgi, D. D., & Ciulla, T. A. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2257604 · Cited by 45
“CFH may also independently act as a protective antioxidant in the RPE [83–85] and participate in lipid metabolism [85,86].”
Background
A Family Affair: Addressing the Challenges of Factor H and the Related Proteins
Poppelaars, F., de Jorge, E. G., Jongerius, I., Baeumner, A. J., Steiner, M., Józsi, M., Toonen, E. J. M., & Pauly, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.660194 · Cited by 45
Bisretinoid-mediated complement activation on retinal pigment epithelial cells is dependent on complement factor H haplotype
Radu, R. A., Hu, J., Jiang, Z., & Bok, D. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.548669 · Cited by 44
“Y402H-substituted CFH has been shown recently to bind malondialdehyde with greatly reduced affinity (13).”
Background
The Landscape of Smart Biomaterial‐Based Hydrogen Therapy
Xu, M., Wu, G., You, Q., & Chen, X. S. (2024) · Advanced Science · doi:10.1002/advs.202401310 · Cited by 43

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: Bennett, Keiryn L.
Scholl, Hendrik P. N.
Issa, Peter Charbel
Tsimikas, Sotirios
Skerka, Christine
Handa, James T.
Zipfel, Peter F.
Witztum, Joseph L.
Binder, Christoph J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-10
Volume: 478
Issue: 7367
Pages: 76-81
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10449
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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Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

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