Abstract
BackgroundThe risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population. While patients with RA also have dyslipidemia, the impact of dyslipidemia on the severity of inflammatory arthritis and associated cardiovascular disease is unclear. Currently, there are conflicting results regarding arthritis incidence in apolipoprotein E (ApoE) deficient mice, which spontaneously exhibit both hyperlipidemia and atherosclerosis. Here, we utilize a distinct approach to investigate the contribution of a hyperlipidemic environment on the development of arthritis and atherosclerosis in mice lacking ApoE.MethodsK/BxN serum transfer-induced arthritis (STIA) was assessed in C57BL/6 (control) and ApoE−/− mice using clinical indices and immunohistochemical staining. Ankle synoviums were processed for flow cytometry. Aortic atherosclerosis was quantitated using Sudan IV staining. Serum cholesterol and cytokine levels were determined via enzymatic and luminex bead-based assays, respectively.ResultsApoE−/− mice developed a sustained and enhanced semi-chronic inflammatory arthritis as compared to control mice. ApoE−/− mice had increased numbers of foamy macrophages, enhanced joint inflammation and amplified collagen deposition versus controls. The presence of arthritis did not exacerbate serum cholesterol levels or significantly augment the level of atherosclerosis in ApoE−/− mice. However, arthritic ApoE−/− mice exhibited a marked elevation of IL-6 as compared to non-arthritic ApoE−/− mice and arthritic C57BL/6 mice.ConclusionsLoss of ApoE potentiates a semi-chronic inflammatory arthritis. This heightened inflammatory response was associated with an increase in circulating IL-6 and in the number of foamy macrophages within the joint. Moreover, the foamy macrophages within the arthritic joint are reminiscent of those within unstable atherosclerotic lesions and suggest a pathologic role for foamy macrophages in propagating arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0912-y) contains supplementary material, which is available to authorized users.
Highlights
The risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population
When the traditional serum transfer-induced arthritis (STIA) model was utilized, we observed no difference in arthritis severity between apolipoprotein E (ApoE)−/− mice and C57BL/6 mice over a 2-week period (Additional file 2)
Our model shows that ApoE is essential for limiting the development of semi-chronic inflammatory arthritis
Summary
The risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population. When foamy macrophages become saturated with oxidized LDL cell death can occur, which results in the release of proinflammatory cellular contents and formation of a necrotic core within the atherosclerotic plaque [5]. The understanding of this process has been facilitated by the use of ApoE knockout mice [6, 7] since functional mutations in ApoE lead to elevations in serum cholesterol levels and premature atherosclerosis in both mice and humans [8, 9]
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