Background/Purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease largely driven by immune complexes and their interaction with FcγRs present on macrophages within the synovium. In RA joint destruction has been associated with an increased lipid oxidation and an altered lipid profile. Apolipoprotein E (Apo E) is an important regulator of LDL levels and its absence strongly elevates LDL in the serum. In the present study we investigated the role of Apo E in inflammation and joint destruction during antigen-induced arthritis (AIA).

Methods: Experimental arthritis (AIA) was induced by injection of 60 µg mBSA into the right knee joint of and wild type (WT) control mice previously immunized with mBSA/CFA. Joint swelling was measured by uptake of ^99m Technecium (^99mTc) and expressed as a ratio of the uptake in the right (injected) and left (non injected) knee joint. Humoral immunity (mBSA antibody titer) was measured by ELISA. WT BM-MΦ were stimulated for 24 hours in vitro with or without 50µg/ml oxLDL and the mRNA expression of the FcγRs was measured by qPCR. Joint inflammation and bone erosion were measured by histological analysis using an arbitrary scale from 0 to 3. TRAP⁺cells were determined using immunohistochemistry.

Results: Apo E^-/- 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) are comparable between the two immunized mouse strains. LDL serum levels were significantly higher in arthritic Apo E^-/- mice and LDL/oxLDL was found within synovial macrophages. At day 21, histology of the knee joints showed less infiltration of inflammatory cells within 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 Apo E^-/- 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). In line with that, ApoE^-/- mice showed a reduction of the number of osteoclasts present at the area of resorption within the arthritic knee joints (36% lower from 20±4 osteoclasts/section in WT mice to 12±5 in ApoE^-/-mice), as measured by image analysis of TRAP staining.

Conclusion: Apo E regulates inflammation and joint destruction during AIA by regulating LDL(oxLDL) levels and macrophage FcγRs expression within the synovium.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/apolipoprotein-e-regulates-inflammation-and-joint-destruction-during-antigen-induced-arthritis-aia/