Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was suppressor of cytokine signaling 3 (Socs3), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, Socs3, was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, cartilage degradation, and joint destruction [1]
To develop a novel synthetic peptide for treating rheumatoid arthritis (RA), we synthesized the novel small molecule peptide AESIS-1 (C82H141N31O31S2) which consists of 19 amino acids (MSLPSPRDGRTDGRTDCTR) and has a molecular weight (MW) of 2121.4
Inflammatory responses in the paw were significantly reduced in collagen-induced arthritis (CIA) mice treated with 25 μg/kg of AESIS-1 compared with those treated with vehicle control
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, cartilage degradation, and joint destruction [1]. Various immune cells, including T cells, B cells, and macrophages, as well as soluble factors such as inflammatory cytokines, autoantibodies, and immune complexes are involved in RA pathogenesis [2] This disease is initiated by dendritic cell–T cell interactions in peripheral lymphoid organs, leading to B-cell activation resulting from proinflammatory cytokine production from T cells, such as interleukin (IL)-4, IL-10, and IL-13. The increased levels of proinflammatory cytokines and chemokines enhance the activation of synovial fibroblasts, which migrate into unaffected regions of the synovium of patients with RA This process, combined with the proliferation of synovial fibroblasts, promotes systemic inflammatory responses [2,3]. Activated synovial fibroblasts, osteoclasts, and infiltrated immune cells release reactive oxygen species (ROS), nitric oxide (NO), and proteases such as matrix metalloproteases (MMP), as well as proinflammatory cytokines that accelerate the inflammatory responses, resulting in bone destruction and cartilage damage [2,4]
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