Chronic inflammation in fibroblast-like synoviocytes (FLSs) induced by pro-inflammatory cytokines such as TNF-a plays a key role in the pathogenesis of rheumatoid arthritis (RA). The neurokinin-1 receptor (NK-1R) is one of the G protein-coupled receptors (GPCRs) mediating the intracellular signalling of substance P (SP). However, the possible implications of NK-1R in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and the pathogenesis of RA have not yet been reported. In the current study, we report that NK-1R is expressed in FLSs. Importantly, NK-1R expression was found to be significantly increased in RA-FLSs compared to normal FLSs. Interestingly, we found that treatment with tumour necrosis factor (TNF)-a increased the expression of NK-1R at both the gene and protein levels. Treatment with the NK-1R antagonist aprepitant reduced TNF-a-induced expression of NADPH oxidase 4 (NOX-4) and generation of reactive oxygen species (ROS) in FLSs. Our results also display that blockage of NF-1R using aprepitant inhibited TNF-a-induced expression and secretion of proinflammatory cytokines, including interleukin-1b (IL-1b), IL-6, and IL-8. Consistently, aprepitant prevented TNF-a-induced expression of matrix metalloproteinases (MMPs), including matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13). Mechanistically, our data demonstrate that treatment with aprepitant inhibited TNF-a-induced phosphorylation and degradation of inhibitor of NF-jB (IjBa). Notably, aprepitant attenuated TNF-a-induced nuclear translocation of nuclear factor jB (NF-jB) p65 and reduced luciferase activity of NF-jB in FLSs. The findings implicated a novel function of NK-1R in RA-FLSs. Blockage of NK-1R using its specific antagonist aprepitant might provide a new therapeutic strategy for RA.

SAPHO syndrome is an autoinflammatory disease with a variety of clinical manifestations, which may be accompanied by other systemic inflammatory diseases in addition to the typical manifestations of common synovitis, acne, pustulosis, hyperostosis, and osteitis. Here, we report the first case of SAPHO syndrome combined with Takayasu arteritis.

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