Abstract
Angiogenesis is a critical process in the formation of new capillaries and a key participant in rheumatoid arthritis (RA) pathogenesis. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays important roles in several cellular functions such as infiltration, migration, and motility. We report significantly higher levels of CXCL13 expression in collagen-induced arthritis (CIA) mice compared with controls and also in synovial fluid from RA patients compared with human osteoarthritis (OA) samples. RA synovial fluid increased endothelial progenitor cell (EPC) homing and angiogenesis, which was blocked by the CXCL13 antibody. By interacting with the CXCR5 receptor, CXCL13 facilitated vascular endothelial growth factor (VEGF) expression and angiogenesis in EPC through the PLC, MEK, and AP-1 signaling pathways. Importantly, infection with CXCL13 short hairpin RNA (shRNA) mitigated EPC homing and angiogenesis, articular swelling, and cartilage erosion in ankle joints of mice with CIA. CXCL13 is therefore a novel therapeutic target for RA.
Highlights
Rheumatoid arthritis (RA) is one of the most common autoimmune disorders, characterized by the accumulation of inflammatory cytokines in the synovial joint, resulting in pannus formation, cartilage degradation, and bone destruction [1]
We report significantly higher levels of CXCL13 expression in collagen-induced arthritis (CIA) mice compared with controls and in synovial fluid from RA patients compared with human osteoarthritis (OA) samples
We examined whether high levels of CXCL13 expression in patients with RA promote the homing and angiogenesis of human circulating Endothelial progenitor cells (EPCs) during RA development and we investigated the signaling pathways that mediate this process
Summary
Rheumatoid arthritis (RA) is one of the most common autoimmune disorders, characterized by the accumulation of inflammatory cytokines in the synovial joint, resulting in pannus formation, cartilage degradation, and bone destruction [1]. CXCL13 is a critical mediator of the homing and activation of cells at lymphoid sites [9]. Overexpression of CXCL13 in lymphoid sites facilitates B-cell infiltration and invasion, leading to increased lymphoid neogenesis [10]. The proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 increase CXCL13 production, leading to maturation of B-cell follicles within the synovium during RA progression [9, 13]. Inhibiting the CXCL13/CXCR5-mediated signaling pathway is a new direction for the treatment of autoimmune disorders [15]. We examined whether high levels of CXCL13 expression in patients with RA promote the homing and angiogenesis of human circulating EPCs during RA development and we investigated the signaling pathways that mediate this process
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