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

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 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.

Etodolac improves collagen induced rheumatoid arthritis in rats by inhibiting synovial inflammation, fibrosis and hyperplasia

“…4a), which represented antibody mediated the classical pathway was activated in present study [15]. As reported, Collectin-12 (Colecl2), Apolipoprotein E (ApoE) and Plasma kallikrein (Klkb1) could trigger complement pathway [16][17][18][19], they might also participate complement system activation in present study.…”

Integrative Brain Transcriptome Analysis Links Complement Component 4 andHSPA2to theAPOEε2 Protective Effect in Alzheimer Disease

“…CR1 is a known receptor for C1q as well as C4A and C4B, and can bind to C1q and C4B simultaneously [50]. ApoE can activate the complement pathway in vitro and cause deposition of C4B, but only in the presence of C1q [51], suggesting that C1q could possibly facilitate an ApoE/C4 interaction through CR1. Future studies are needed to confirm the binding interactions among members of this network, and determine whether this network is disrupted in the APOE genotype dependent manner and, if so, elucidate the nature of the interaction between the complement pathway and ε2.…”

The Specific Mechanism of TREM2 Regulation of Synaptic Clearance in Alzheimer’s Disease

“…C1q and APOE were previously thought to act separately and perform independent tasks in many tissue contexts. Recent studies have shown a correlation between C1q and APOE ( 66 ). Currently, C1q has been shown to colocalize with APOE in the brain in human AD ( 67 ).…”