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Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

Nature volume 478, pages 76–81 (2011)Cite this article

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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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Figure 1: CFH specifically binds to MDA modifications.
Figure 2: The SCR7 domain of CFH is critical for MDA binding.
Figure 3: CFH binds to MDA epitopes present in AMD lesions, on necrotic cells and apoptotic blebs.
Figure 4: CFH inactivates complement on MDA-bearing surfaces.
Figure 5: CFH neutralizes proinflammatory effects of MDA.

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Acknowledgements

We are indebted to M. Ozsvar-Kozma for technical assistance, S. Hälbich for performing the surface plasmon resonance analysis, A. Hartmann for purification of CFH variants from patient plasma, C. Mannhalter for help with genotyping, and E. N. Montano. This work was supported by the Austrian Academy of Sciences, a BRIDGE grant from the Austrian Research Promotion Agency, the SFB Lipotox F30 of the Austrian Science Fund (C.J.B.); NIH grants HL088093 (C.J.B., S.T., J.L.W.), RO1 HL086599 (K.H., J.L.W.), EY14005, EY019044 (J.T.H.); the Edward N. & Della L. Thome Memorial Foundation Awards Program in AMD Research, Research to Prevent Blindness (Wilmer Eye institute) (J.T.H.); the Deutsche Forschungsgemeinschaft (P.F.Z., C.S.); the ProRetina Foundation (N.L., P.F.Z., C.S.); the Fondation Leducq (C.J.B., S.T., J.L.W.); the Wynn-Gund Translational Research Acceleration Program Enhanced Research and Clinical Training Award, National Neurovision Research Institute – Foundation Fighting Blindness, Macular Degeneration Research Award, American Health Assistance Foundation (H.P.N.S.); European Commission and the Seventh European Community Framework Program, Marie Curie Intra-European Fellowship (P.C.I.). K.H. was supported by the Scientist Development Grant 0630228N of the American Heart Association. J.T.H. is the Robert Bond Welch Professor. We thank all patients for participation.

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Authors and Affiliations

  1. Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, 1090 Vienna, Austria

    David Weismann, Karsten Hartvigsen, Keiryn L. Bennett, Giulio Superti-Furga & Christoph J. Binder

  2. Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria

    David Weismann, Karsten Hartvigsen, Hubert Brandstätter & Christoph J. Binder

  3. Department of Medicine, University of California at San Diego, La Jolla, 92093, California, USA

    Karsten Hartvigsen, Sotirios Tsimikas, Joseph L. Witztum & Christoph J. Binder

  4. Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute and Friedrich Schiller University, 07745 Jena, Germany

    Nadine Lauer, Christine Skerka & Peter F. Zipfel

  5. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Hendrik P. N. Scholl, Marisol Cano & James T. Handa

  6. Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford OX3 9DU, UK

    Peter Charbel Issa

  7. Octapharma PPGmbH, Research & Development, 1100 Vienna, Austria

    Hubert Brandstätter

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  1. David Weismann
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Contributions

D.W. and C.J.B. conceived the project and designed and analysed the experiments with contributions from J.L.W., P.F.Z., J.T.H., G.S.-F. and C.S.; D.W. performed most of the experiments, with contributions from K.H., N.L., K.L.B., M.C., S.T. and H.B.; H.P.N.S. and P.C.I. obtained and provided AMD plasma samples; D.W. and C.J.B. wrote the manuscript with contributions from J.L.W., P.F.Z. and J.T.H.

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Correspondence to Christoph J. Binder.

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Weismann, D., Hartvigsen, K., Lauer, N. et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478, 76–81 (2011). https://doi.org/10.1038/nature10449

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