Apolipoprotein E Triggers Complement Activation in Joint Synovial Fluid of Rheumatoid Arthritis Patients by Binding C1q

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  • Leonie M Vogt, Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 21428 Malmö, Sweden.
  • ,
  • Ewa Kwasniewicz, Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 21428 Malmö, Sweden.
  • ,
  • Simone Talens, Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 21428 Malmö, Sweden.
  • ,
  • Carsten Scavenius
  • Ewa Bielecka, Malopolska Centre of Biotechnology, Jagiellonian University, PL-30-387 Kraków, Poland.
  • ,
  • Kristina N Ekdahl, Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden.
  • ,
  • Jan J Enghild
  • Matthias Mörgelin, Division of Infection Medicine, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden.
  • ,
  • Tore Saxne, Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, S-22185 Lund, Sweden.
  • ,
  • Jan Potempa, Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202.
  • ,
  • Anna M Blom, Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, 21428 Malmö, Sweden; anna.blom@med.lu.se.

We identified apolipoprotein E (ApoE) as one of the proteins that are found in complex with complement component C4d in pooled synovial fluid of rheumatoid arthritis (RA) patients. Immobilized human ApoE activated both the classical and the alternative complement pathways. In contrast, ApoE in solution demonstrated an isoform-dependent inhibition of hemolysis and complement deposition at the level of sC5b-9. Using electron microscopy imaging, we confirmed that ApoE interacts differently with C1q depending on its context; surface-bound ApoE predominantly bound C1q globular heads, whereas ApoE in a solution favored the hinge/stalk region of C1q. As a model for the lipidated state of ApoE in lipoprotein particles, we incorporated ApoE into phosphatidylcholine/phosphatidylethanolamine liposomes and found that the presence of ApoE on liposomes increased deposition of C1q and C4b from serum when analyzed using flow cytometry. In addition, posttranslational modifications associated with RA, such as citrullination and oxidation, reduced C4b deposition, whereas carbamylation enhanced C4b deposition on immobilized ApoE. Posttranslational modification of ApoE did not alter C1q interaction but affected binding of complement inhibitors factor H and C4b-binding protein. This suggests that changed ability of C4b to deposit on modified ApoE may play an important role. Our data show that posttranslational modifications of ApoE alter its interactions with complement. Moreover, ApoE may play different roles in the body depending on its solubility, and in diseased states such as RA, deposited ApoE may induce local complement activation rather than exert its typical role of inhibition.

OriginalsprogEngelsk
TidsskriftJournal of Immunology
Vol/bind204
Nummer10
Sider (fra-til)2779-2790
Antal sider12
ISSN0022-1767
DOI
StatusUdgivet - 2020

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