Background Rheumatoid arthritis (RA) is a chronic inflammatory disease largely driven by immune complexes and their interaction with FcγRs on synovial macrophages. In RA, joint destruction has been associated with high levels of cholesterol (LDL) which become oxidised (oxLDL) within the inflamed synovium. Apolipoprotein E (ApoE) regulates LDL levels and its absence strongly elevates LDL in the serum. In this study we investigated the role of ApoE in inflammation and joint destruction during antigen-induced arthritis (AIA).
Materials and methods Experimental arthritis was induced by injection of mBSA into the right knee joint of ApoE-/- and wild type (WT) mice previously immunised with mBSA/CFA. Joint swelling was measured by 99m Technecium (99mTc) uptake and expressed as a ratio of the uptake in the right (injected) and left (non injected) knee joint. Serum mBSA antibody titer was measured by ELISA. WT BM-MΦ were stimulated for 24 hours in vitro with or without 50 µg/ml oxLDL and the FcγRs mRNA expression was measured by qPCR. Joint inflammation and damage were measured by histology using an arbitrary scale from 0 to 3.
Results ApoE-/- mice showed significantly less joint swelling at day 1, 3 and 7 after AIA induction compared to WT controls (21%, 17%, 18% lower, respectively). Serum mBSA antibody levels (total IgG, IgG1, IgG2a and IgG2b) were comparable between WT and ApoE-/-mice. LDL serum levels were significantly higher in ApoE-/- mice and LDL/oxLDL was found within synovial macrophages. At day 21, histology showed less inflammatory cells within the synovium and joint cavity (22% and 44% lower, respectively) in the ApoE-/- mice compared to WT controls. WT BM-MΦ stimulated with oxLDL displayed a significant down-regulation of mRNA levels of FcγR I and FcγR II when compared to their non stimulated controls (1,7 and 2,3 fold change, respectively). Joint destruction was significantly reduced in the ApoE-/- mice, as indicated by the reduction of chondrocyte death (32% reduction) and bone erosion (25% reduction from 1.5±0.2 to 1.1±0.1).
Conclusions ApoE stimulates joint destruction during AIA by lowering LDL/oxLDL levels, thereby promoting Fcγ- mediated macrophage activation within the synovium.