Jinwujiangu Capsule Treats Fibroblast-Like Synoviocytes of Rheumatoid Arthritis by Inhibiting Pyroptosis via the NLRP3/CAPSES/GSDMD Pathway

Abstract

Jinwujiangu capsule (JWJGC) is a traditional Chinese medicine formula used to treat rheumatoid arthritis (RA). However, whether its mechanism is associated with pyroptosis remains unclear. In this study, the ability of JWJGC to inhibit the growth of fibroblast-like synoviocytes of RA (RA-FLS) through pyroptosis was evaluated. The cells isolated from patients with RA were identified by hematoxylin and eosin (H&E) staining, immunohistochemistry, and flow cytometry. After RA-FLS were treated with different concentrations of JWJGC-containing serum, the cell proliferation inhibition rate, expression of caspase-1/3/4/5, NOD-like receptor protein 3 (NLRP3), gasdermin-D (GSDMD), and apoptosis-associated speck-like protein containing a CARD (ASC), concentrations of interleukin-1β (IL-1β) and interleukin-18 (IL-18), the activity of lactic dehydrogenase (LDH), and pyroptosis were evaluated. The results showed that JWJGC increased the proliferative inhibition rate, decreased the expression of caspase-1/3/4/5, GSDMD, NLRP3, and ASC, suppressed the expression of IL-1β and IL-18, induced the activity of LDH, and downregulated the number of double-positive FITC anti-caspase-1 and PI. Generally, our findings suggest that JWJGC can regulate NLRP3/CAPSES/GSDMD in treating RA-FLS through pyroptosis.

New Potentiality of Bioactive Substances: Regulating the NLRP3 Inflammasome in Autoimmune Diseases

“…Several bioactive substances with unidentified specific targets have been found to exert their effects by regulating the TLR4/NLRP3/NF-κB/GSDMD signaling pathway. These include traditional Chinese medicine formulas such as the Jinwujiangu capsule for treating RA [196], Baihu-Guizhi decoction [197], and Qi-Sai-Er-Sang-Dang-Song decoction [198]. Additionally, bioactive compounds extracted from plants, such as the monomer derivative of paeoniflorin [199], wedelolactone derived from Xanthium sibiricum [200], licoriceprocessed DGN products containing Huangruixiang [201], a combination of mangiferin and cinnamic acid [202], punicalagin [203], tectoridin [204], strychnine combined with Atractylodes Macrocephala [205], and pinocembrin from the genus Pinus [206], have also shown activity through this pathway.…”

Can pyroptosis be a new target in rheumatoid arthritis treatment?

“…Ling et al. found that Hmong Jin Wu Jian Wu Bone Capsules were able to inhibit fibroblast-like synoviocyte (FLS) pyroptosis through the NLRP3/caspase/GSDMD pathway in the treatment of RA ( 95 ). Ge et al.…”

“…Ling et al found that Hmong Jin Wu Jian Wu Bone Capsules were able to inhibit fibroblast-like synoviocyte (FLS) pyroptosis through the NLRP3/caspase/GSDMD pathway in the treatment of RA (95). Ge et al found that punicalagin was able to reduce the expression of NLRP3 inflammatory in collagen-induced arthritis (CIA) mice and inhibit the occurrence of pyroptosis, resulting in an anti-inflammatory effect (9).…”

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation

“…Studies have shown that GSDMD deletion or inhibition notably decreases pyroptosis and remarkably protect mice from sepsis, which is a fatal condition requiring urgent medical solutions ( 12 – 14 ). In addition, GSDMD acts as an effector of inflammasome signaling and is implicated in several human diseases, including nonalcoholic steatohepatitis ( 15 ), cardiovascular disease ( 16 ), inflammatory bowel disease ( 17 ), type II diabetes ( 17 , 18 ), rheumatoid arthritis ( 19 ), cancer ( 20 , 21 ), and Alzheimer’s disease ( 22 ). Consequently, on account of the crucial function of GSDMD in pyroptosis, it has emerged as an ideal and attracting target for therapeutic intervention of inflammasome-driven diseases.…”