Complement factor H binds to human serum apolipoprotein E and mediates complement regulation on high-density lipoprotein particles

Karita Haapasalo, Kok van Kessel, Eija Nissilä, Jari Metso, Tiira Johansson, Sini Miettinen, Markku Varjosalo, Juha Kirveskari, Pentti Kuusela, Angeliki Chroni, Matti Jauhiainen, Jos A G Van Strijp, T Sakari Jokiranta, CPM van Kessel

Research output: Contribution to journalArticleAcademicpeer-review

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 have previously shown 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, 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 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.

Original languageEnglish
JournalJournal of Biological Chemistry
DOIs
Publication statusPublished - 2015

Keywords

  • Complement
  • Complement system
  • Factor H
  • Apolipoprotein E
  • High density lipoprotein
  • Inflammation

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