Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease

Abstract

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and RA interstitial lung disease (ILD) is a severe complication of RA. This investigation aims to determine the effect and underlying mechanism of osthole (OS), which could be extracted from Cnidium , Angelica , and Citrus plants and evaluate the role of transglutaminase 2 (TGM2) in RA and RA‐ILD. In this work, OS downregulated TGM2 to exert its additive effect with methotrexate and suppress the proliferation, migration, and invasion of RA‐fibroblast‐like synoviocytes (FLS) by attenuating NF‐κB signaling, resulting in the suppression of RA progression. Interestingly, WTAP‐mediated N6‐methyladenosine modification of TGM2 and Myc‐mediated WTAP transcription cooperatively contributed to the formation of a TGM2/Myc/WTAP‐positive feedback loop through upregulating NF‐κB signaling. Moreover, OS could downregulate the activation of the TGM2/Myc/WTAP‐positive feedback circuit. Furthermore, OS restrained the proliferation and polarization of M2 macrophages to inhibit the aggregation of lung interstitial CD11b + macrophages, and the effectiveness and non‐toxicity of OS in suppressing RA and RA‐ILD progression were verified in vivo. Finally, bioinformatics analyses validated the importance and the clinical significance of the OS‐regulated molecular network. Taken together, our work emphasized OS as an effective drug candidate and TGM2 as a promising target for RA and RA‐ILD treatment.

Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease

“…Sendo et al recently found CD11b + Gr − 1 dim tolerogenic dendritic cell-like cells, which are distinctive suppressive myeloid cells that differentiate from monocytic myeloid-derived suppressor cells in SKG mice with ILD [161]. The CIA mouse model also represented the increased aggregation of CD11b + interstitial macrophages in the subpleural inflammation area [162]. In addition, the authors demonstrated that tofacitinib triggered the expansion of MDSCs in the lungs and inhibited ILD progression in SKG mice [163].…”

Efficacy and safety of Duhuo-Jisheng decoction in rheumatoid arthritis: A systematic review and meta-analysis of 42 randomized controlled trials

“…[90] Similarly, it was found that columbianadin can inhibit the secretion of the inflammatory cytokine IL-17A, promote its differentiation towards treg cells, and promote the secretion of anti-inflammatory cytokines. [91] Several studies have revealed that osthole, an active ingredients of Radix Angelicae Pubescentis (Du Huo), can inhibit the proliferation, migration, and invasion of RA fibroblast like synovial cells by weakening NF-κB signaling, [92] and activate AMPK to inhibit NLRP3 inflammasome activation. [93] Additionally, many inflammatory factors, including IL-1β, IL-6, TNF-α, etc., were found to be decreased by active ingredients or extracts in DJD in both in vivo and in vitro experiments of RA, such as senkyunolide I, [94] 18β-Glycyrrhetinic acid, [95] liquiritin, [96] polysaccharide from Radix Angelicae sinensis (Dang Gui), [97] paeoniflorin, [98][99][100][101][102] paeoniflorin-6'-O-benzene sulfonate, [103] curcumin, [104] the total saponins of Radix Achyranthis bidentatae (Niu Xi), [105] supercritical carbon dioxide extraction of Radix Achyranthis bidentatae (Niu Xi), [106] polysaccharide from Radix Saposhnikoviae divaricatae (Fang Feng), [107,108] and Radix Saposhnikoviae divaricatae (Fang Feng).…”