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Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

2011; Nature Portfolio; Volume: 478; Issue: 7367 Linguagem: Inglês

10.1038/nature10449

1476-4687

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

Atherosclerosis and Cardiovascular Diseases

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. Age-related macular degeneration (AMD) is a leading cause of blindness in older people. A polymorphism in complement factor H (CFH) has been strongly associated with the disease, but the mechanism of the association has been unclear. Here it is shown that CFH binds specifically to the lipid peroxidation product, malondialdehyde, which builds up in AMD as a result of oxidative stress. Malondialdehyde and malondialdehyde-modified proteins induce inflammatory responses; CFH neutralizes this inflammatory potential both in vitro and in the mouse retina. A common CFH polymorphism associated with AMD leads to impaired binding to malondialdehyde, potentially explaining why homozygous individuals with this polymorphism have a 6–7-fold increased risk of developing the condition.