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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Binding Sites / genetics
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Complement Factor H / genetics
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Complement Factor H / immunology
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Complement Factor H / metabolism*
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Complement Inactivator Proteins / genetics
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Complement Inactivator Proteins / immunology
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Complement Inactivator Proteins / metabolism
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Complement System Proteins / immunology
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Complement System Proteins / metabolism
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Enzyme-Linked Immunosorbent Assay
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Epitopes / chemistry
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Epitopes / metabolism*
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Female
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Humans
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / pathology
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Lipid Peroxidation
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Macrophages, Peritoneal / metabolism
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Macular Degeneration / metabolism
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Macular Degeneration / pathology
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Male
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Malondialdehyde / antagonists & inhibitors
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Malondialdehyde / chemistry
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Malondialdehyde / immunology
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Malondialdehyde / metabolism*
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Mice
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Mice, Inbred C57BL
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Mutation / genetics
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Necrosis
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Oxidative Stress*
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Protein Binding / genetics
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Protein Structure, Tertiary
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Retina / metabolism
Substances
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Complement Inactivator Proteins
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Epitopes
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Malondialdehyde
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Complement Factor H
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Complement System Proteins