Antagonism of NK-1R using aprepitant suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. Issue 1 (4th December 2019)

• Record Type: Journal Article
• Authors: Liu, Xiaoping; Zhu, Yuelan; Zheng, Wei; Qian, Tangliang; Wang, Haiyu; Hou, Xiujuan
• Is Part Of: Artificial cells, nanomedicine, and biotechnology. Volume 47:Issue 1(2019)
• Page Start: 1628
• Page End: 1634
• Publication Date: 2019-12-04
• Subjects: Rheumatoid arthritis -- aprepitant -- TNF-α -- matrix metalloproteinases -- NK-1R -- NF-κB; Artificial cells -- Periodicals; Nanotechnology -- Periodicals; Blood substitutes -- Periodicals; Tissue engineering -- Periodicals; Molecules -- Periodicals; Biotechnology -- Periodicals; 615.39
• DOI: 10.1080/21691401.2019.1573177
• Languages: English
• ISSNs: 2169-1401

Abstract

Abstract: Chronic inflammation in fibroblast-like synoviocytes (FLSs) induced by pro-inflammatory cytokines such as TNF-α 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)-α increased the expression of NK-1R at both the gene and protein levels. Treatment with the NK-1R antagonist aprepitant reduced TNF-α-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-α-induced expression and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and IL-8. Consistently, aprepitant prevented TNF-α-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-α-induced phosphorylation and degradation of inhibitor of NF-κB (IκBα). Notably, aprepitant attenuated TNF-α-induced nuclear translocation of nuclear factor κB (NF-κB) p65 and reduced luciferase activity of NF-κB 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.