Abstract
Rheumatoid arthritis (RA), a chronic systemic inflammatory disorder that principally attacks synovial joints, afflicts over 2 million people in the United States. Interleukin (IL)-17 is considered to be a master cytokine in chronic, destructive arthritis. Levels of the ganglioside GM3, one of the most primitive glycosphingolipids containing a sialic acid in the structure, are remarkably decreased in the synovium of patients with RA. Based on the increased cytokine secretions observed in in vitro experiments, GM3 might have an immunologic role. Here, to clarify the association between RA and GM3, we established a collagen-induced arthritis mouse model using the null mutation of the ganglioside GM3 synthase gene. GM3 deficiency exacerbated inflammatory arthritis in the mouse model of RA. In addition, disrupting GM3 induced T cell activation in vivo and promoted overproduction of the cytokines involved in RA. In contrast, the amount of the GM3 synthase gene transcript in the synovium was higher in patients with RA than in those with osteoarthritis. These findings indicate a crucial role for GM3 in the pathogenesis and progression of RA. Control of glycosphingolipids such as GM3 might therefore provide a novel therapeutic strategy for RA.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissues in multiple joints, leading to joint destruction [1]
GM3 is Increased in the Synovium of RA Patients Infiltration of multi-stratified synoviocytes and inflammatory cells into synovial tissues is commonly observed in RA patients (Figure 2A)
In contrast to the amount of GM3 production in the synovium, GM3 synthase (GM3S) mRNA transcription was increased in the synovium and in the peripheral blood mononuclear cells (PBMCs) of RA patients (Figure 2D)
Summary
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissues in multiple joints, leading to joint destruction [1]. Th17 cells (a subset of CD4+ T cells that are distinct from Th1 and Th2) and regulatory T cells are suggested to mediate inflammation and have a key role in the pathogenesis of RA [3]. The cytokine IL-17 enhances the inflammation associated with RA and contributes to the pathogenesis of RA by inducing monocyte migration into the inflamed synovial tissue [5,6]. High-level production of proinflammatory cytokines, such as IL-1 and TNFa, in the synovium results from an interaction between monocytes or macrophage cells and synoviocytes [7]. The regulatory mechanism of Th17 cells in RA, remains unclear
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