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J Biol Chem. 2015 Nov 27;290(48):28977-87. doi: 10.1074/jbc.M115.669226. Epub 2015 Oct 14.

Complement Factor H Binds to Human Serum Apolipoprotein E and Mediates Complement Regulation on High Density Lipoprotein Particles.

Author information

  • 1From the Department of Bacteriology and Immunology, Haartman Institute, and Research Programs Unit, Immunobiology, University of Helsinki, FIN-00014 Helsinki, Finland, Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands, K.J.Haapasalo-Tuomainen@umcutrecht.nl.
  • 2Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
  • 3From the Department of Bacteriology and Immunology, Haartman Institute, and Research Programs Unit, Immunobiology, University of Helsinki, FIN-00014 Helsinki, Finland.
  • 4Department of Molecular Medicine, National Institute for Health and Welfare, Biomedicum, FI-00290 Helsinki, Finland.
  • 5University of Helsinki, Institute of Biotechnology, 00014 Helsinki, Finland.
  • 6HUSLAB, Helsinki University Central Hospital Laboratory, 00290 Helsinki, Finland, and.
  • 7Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos," 15310 Athens, Greece.

Abstract

The alternative pathway of complement is an important part of the innate immunity response against foreign particles invading the human body. To avoid damage to host cells, it needs to be efficiently down-regulated by plasma factor H (FH) as exemplified by various diseases caused by mutations in its domains 19-20 (FH19-20) and 5-7 (FH5-7). These regions are also the main interaction sites for microbial pathogens that bind host FH to evade complement attack. We previously showed that inhibition of FH binding by a recombinant FH5-7 construct impairs survival of FH binding pathogens in human blood. In this study we found that upon exposure to full blood, the addition of FH5-7 reduces survival of, surprisingly, also those microbes that are not able to bind FH. This effect was mediated by inhibition of complement regulation and subsequently enhanced neutrophil phagocytosis by FH5-7. We found that although FH5-7 does not reduce complement regulation in the actual fluid phase of plasma, it reduces regulation on HDL particles in plasma. Using affinity chromatography and mass spectrometry we revealed that FH interacts with serum apolipoprotein E (apoE) via FH5-7 domains. Furthermore, binding of FH5-7 to HDL was dependent on the concentration of apoE on the HDL particles. These findings explain why the addition of FH5-7 to plasma leads to excessive complement activation and phagocytosis of microbes in full anticoagulated blood. In conclusion, our data show how FH interacts with apoE molecules via domains 5-7 and regulates alternative pathway activation on plasma HDL particles.

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

apolipoprotein E (ApoE); complement; complement system; factor H; high density lipoprotein (HDL); inflammation

PMID:
26468283
[PubMed - indexed for MEDLINE]
PMCID:
PMC4661410
[Available on 2016-11-27]
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