Antagonism of NK-1R using aprepitant suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes.

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.

• Authors: Xiaoping Liu, Yuelan Zhu, Wei Zheng, Tangliang Qian, Haiyu Wang, Xiujuan Hou
• Journal: Artificial cells, nanomedicine, and biotechnology (Artif Cells Nanomed Biotechnol) Vol. 47 Issue 1 Pg. 1628-1634 (Dec 2019) ISSN: 2169-141X [Electronic] England
• PMID: 31010320 (Publication Type: Journal Article)

Chemical References

• NF-kappa B
• Neurokinin-1 Receptor Antagonists
• Receptors, Neurokinin-1
• Tumor Necrosis Factor-alpha
• NF-KappaB Inhibitor alpha
• Aprepitant
• Matrix Metalloproteinase 13
• Matrix Metalloproteinase 3

Topics

• Aprepitant (pharmacology, therapeutic use)
• Arthritis, Rheumatoid (drug therapy, genetics, metabolism, pathology)
• Fibroblasts (pathology)
• Gene Expression Regulation (drug effects)
• Humans
• Inflammation (drug therapy)
• Matrix Metalloproteinase 13 (metabolism)
• Matrix Metalloproteinase 3 (metabolism)
• NF-KappaB Inhibitor alpha (metabolism)
• NF-kappa B (metabolism)
• Neurokinin-1 Receptor Antagonists (pharmacology, therapeutic use)
• Oxidative Stress (drug effects)
• Receptors, Neurokinin-1 (genetics, metabolism)
• Signal Transduction (drug effects)
• Synoviocytes (drug effects, metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism)