Nitidine chloride inhibits fibroblast like synoviocytes-mediated rheumatoid synovial inflammation and joint destruction by targeting KCNH1

• Published in: International immunopharmacology 2021-12, Vol.101 (Pt A), p.108273-108273, Article 108273
• Main Authors: Shen, Chuyu, Kuang, Yu, Xu, Shudi, Li, Ruiru, Wang, Jingnan, Zou, Yaoyao, Wang, Cuicui, Xu, Siqi, Liang, Liuqin, Lin, Changsong, Xiao, Youjun, Xu, Hanshi
• Format: Article
• Language: English
• Subjects: Aggression; AKT protein; Animals; Anticancer properties; Apoptosis; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Autoimmune diseases; Benzophenanthridines - pharmacology; Benzophenanthridines - therapeutic use; Boyden chamber; Cell proliferation; Cells, Cultured; Chemical compounds; Chlorides; Collagen; Collagenase 3; Cytokines; Destruction; Enzyme-linked immunosorbent assay; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - metabolism; Evaluation; Female; Fibroblast-like synoviocyte; Fibroblasts; Fibroblasts - immunology; Fibroblasts - metabolism; Gene expression; Gene Knockdown Techniques; Gene sequencing; Healthy Volunteers; Herbal medicine; Humans; Immunohistochemistry; Inflammation; Interleukin 6; Interleukin 8; Interstitial collagenase; Joints (anatomy); KCNH1; Lamellipodia; Male; Matrix metalloproteinase; Mice; Middle Aged; Nitidine chloride; Patients; Pharmacology; Phosphorylation; Polymerase chain reaction; Primary Cell Culture; Pseudopodia; Rheumatoid arthritis; Synovial Membrane - drug effects; Synovial Membrane - immunology; Synovial Membrane - pathology; Synoviocytes; Synoviocytes - drug effects; Synoviocytes - immunology; Target recognition; Tumor necrosis factor-α; Tumors
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.108273

•NC treatment reduced synovial inflammation and joint destruction of RA.•KCNH1 is the new targeting gene of NC on RA FLS.•KCNH1 is involved in the regulation of abnormal biological behavior of RA FLS. Nitidine chloride (NC), a natural small molecular compound from traditional Chinese herbal medicine zanthoxylum nitidum, has been shown to exhibit anti-tumor effect. However, its role in autoimmune diseases such as rheumatoid arthritis (RA) is unknown. Here, we investigate the effect of NC in controlling fibroblast-like synoviocytes (FLS)-mediated synovial inflammation and joint destruction in RA and further explore its underlying mechanism(s). FLSs were separated from synovial tissues obtained from patients with RA. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression was measured using quantitative RT-PCR. ELISA was used to measure the levels of cytokines and MMPs. Cell proliferation was detected using EdU incorporation. Migration and invasion were evaluated by Boyden chamber assay. RNA sequencing analysis was used to identify the target of NC. Collagen-induced arthritis (CIA) model was used to evaluate the in vivo effect of NC. NC treatment reduced the proliferation, migration, invasion, and lamellipodia formation but not apoptosis of RA FLSs. We also demonstrated the inhibitory effect of NC on TNF-α-induced expression and secretion of IL-6, IL-8, CCL-2, MMP-1 and MMP-13. Furthermore, we identified KCNH1, a gene that encodes ether-à-go-go-1 channel, as a novel targeting gene of NC in RA FLSs. KCNH1 expression was increased in FLSs and synovial tissues from patients with RA compared to healthy controls. KCNH1 knockdown or NC treatment decreased the TNF-α-induced phosphorylation of AKT. Interestingly, NC treatment ameliorated the severity of arthritis and reduced synovial KCNH1 expression in mice with CIA. Our data demonstrate that NC treatment inhibits aggressive and inflammatory actions of RA FLSs by targeting KCNH1 and sequential inhibition of AKT phosphorylation. Our findings suggest that NC might control FLS-mediated rheumatoid synovial inflammation and joint destruction, and be a novel therapeutic agent for RA.