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Apolipoprotein E triggers complement activation in joint synovial fluid of rheumatoid arthritis patients by binding C1q

Vogt, Leonie M. LU ; Kwasniewicz, Ewa LU ; Talens, Simone LU ; Scavenius, Carsten ; Bielecka, Ewa LU ; Ekdahl, Kristina N. ; Enghild, Jan J. ; Mörgelin, Matthias LU ; Saxne, Tore LU and Potempa, Jan , et al. (2020) In Journal of Immunology 204(10). p.2779-2790
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
204
issue
10
pages
12 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:85084382154
  • pmid:32253242
ISSN
0022-1767
DOI
10.4049/jimmunol.1900372
language
English
LU publication?
yes
id
1eb9d04c-7340-4e05-afde-ac1588cf3aa1
date added to LUP
2020-06-02 16:38:46
date last changed
2024-05-15 11:39:59
@article{1eb9d04c-7340-4e05-afde-ac1588cf3aa1,
  abstract     = {{<p>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.</p>}},
  author       = {{Vogt, Leonie M. and Kwasniewicz, Ewa and Talens, Simone and Scavenius, Carsten and Bielecka, Ewa and Ekdahl, Kristina N. and Enghild, Jan J. and Mörgelin, Matthias and Saxne, Tore and Potempa, Jan and Blom, Anna M.}},
  issn         = {{0022-1767}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{2779--2790}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of Immunology}},
  title        = {{Apolipoprotein E triggers complement activation in joint synovial fluid of rheumatoid arthritis patients by binding C1q}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1900372}},
  doi          = {{10.4049/jimmunol.1900372}},
  volume       = {{204}},
  year         = {{2020}},
}