Abstract
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor that plays a pivotal role in cellular defense against oxidative injury. Nrf2 signaling is involved in attenuating autoimmune disorders such as rheumatoid arthritis (RA). B cells play several roles in the pathogenesis of RA, such as in autoantibody production, antigen presentation, and T-cell activation. We investigated the anti-arthritic mechanisms of sulforaphane, an activator of Nrf2, in terms of its effect on B cells. To investigate the effect of sulforaphane on collagen-induced arthritis (CIA), sulforaphane was administered intraperitoneally after CIA induction. Hematoxylin and eosin-stained sections were scored for inflammation, pannus invasion, and bone and cartilage damage. We assessed the expression levels of inflammation-related factors by real-time PCR and the levels of various IgG subclasses by enzyme-linked immunosorbent assay. Sulforaphane treatment reduced the arthritis score and the severity of histologic inflammation in CIA mice. The joints from sulforaphane-treated CIA mice showed decreased expression of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, receptor activator of NF-κB ligand, and tartrate-resistant acid phosphatase. Sulforaphane-treated mice showed lower circulating levels of type-II-collagen-specific IgG, IgG1, and IgG2a. In vitro, sulforaphane treatment significantly reduced the differentiation of lipopolysaccharide-stimulated murine splenocytes into plasma B cells and germinal-center B cells. Finally, sulforaphane significantly inhibited the production of IL-6, TNF-α, and IL-17 by human peripheral blood mononuclear cells stimulated with an anti-CD3 monoclonal antibody in a dose-dependent manner. Inhibition of differentiation into plasma B and Germinal Center B cells may be the mechanism underlying the anti-arthritic effect of sulforaphane.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by infiltration of immune cells into the hyperplastic synovium, which manifests as pannus formation
We investigated the effect of sulforaphane on inflammation and joint destruction in collagen-induced arthritis (CIA) mice, which is dependent on autoantibody production [16]
IL-6, IL-17, and tumor necrosis factor-α (TNF-α) are proinflammatory cytokines that participate in the inflammatory process in the RA synovium and have systemic effects [17, 18]
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by infiltration of immune cells (such as T and B cells) into the hyperplastic synovium, which manifests as pannus formation. The disease eventually leads to progressive joint destruction and reduces quality of life. The importance of B cells and plasma cells in the development and progression of RA was suggested [1] by detection of autoantibodies such as anti-cyclic citrullinated peptide (antiCCP) and anti-rheumatoid factor (anti-RF) in patients with RA [2, 3]. As autoantibody production leads to immune complex formation and cytokine release [7], plasma cell hyperreactivity is viewed as a key component of the development and perpetuation of RA [8, 9]. B-cell depletion is used to treat RA [10, 11]
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