Targeting p38 MAPK signaling pathway and neutrophil extracellular traps: An important anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis

被引:1
|
作者
Li, Yang [1 ,2 ]
Liu, Jian [1 ,3 ]
Sun, Yue [1 ,3 ]
Hu, Yuedi [1 ,2 ]
Cong, Chengzhi [1 ,2 ]
Chen, Yiming [1 ,2 ]
Fang, Yanyan [1 ,3 ]
机构
[1] Anhui Univ Chinese Med, Affiliated Hosp 1, Dept Rheumatol, Hefei 230031, Anhui, Peoples R China
[2] Anhui Univ Chinese Med, Clin Med Sch 1, Hefei 230038, Anhui, Peoples R China
[3] Anhui Acad Chinese Med, Inst Rheumatol, Hefei 230031, Anhui, Peoples R China
关键词
Rheumatoid arthritis; Huangqin Qingre Chubi Capsule; Inflammation; P38 MAPK signaling pathway; Neutrophil extracellular traps;
D O I
10.1016/j.intimp.2025.114112
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Rheumatoid arthritis (RA) is a common chronic autoimmune disease. Neutrophils release and their extracellular traps (NETs) tend to result in synovial inflammation and cartilage damage. Huangqin Qingre Chubi Capsule (HQC) is an important herbal formulation for RA treatment and has been used for many years. This study applied an interdisciplinary and integrated strategy combining clinical data, integrative bioinformatics, molecular modeling, and both in vitro and in vivo experiments to elucidate the efficacy and potential anti-inflammatory mechanisms of HQC for RA. Retrospective clinical data mining demonstrated that patients with RA treated with HQC exhibited recovery of immuno-inflammatory markers and self-perception. By applying network pharmacological analysis, molecular docking, molecular dynamics simulation, and cellular thermal shift assays, we determined that HQC can directly bind to MAPK14 and target p38 MAPK signaling pathway and NETs formation. Treatment of an adjuvant-induced arthritis rat model combining damp-heat patterns using HQC demonstrated it's effectiveness in reducing the severity of inflammatory arthritis in a dose-dependent manner and downregulated phosphorylation of p38 MAPK and NETs release. In vitro co-culture system mimicking inflammatory microenvironment of RA in vivo revealed that crosstalk between neutrophils (PMNs) and fibroblast- like synoviocytes (FLSs) was manifested by activation of p38 MAPK signaling pathway, release of NETs, and amplification of inflammation, which was blocked by HQC. Mechanistic validation using the p38 MAPK agonist diprovocim demonstrated that HQC inhibited NET formation by modulating the p38 MAPK pathway (mainly by inhibiting its phosphorylation) to exert anti-inflammatory effects. In conclusion, our interdisciplinary and integrated study demonstrated that HQC can target the p38 MAPK signaling pathway to inhibit NET formation and inflammatory response, thereby blocking the crosstalk between PMNs and FLSs to ameliorating RA.
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页数:20
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