PMID- 36209953 OWN - NLM STAT- MEDLINE DCOM- 20221109 LR - 20221109 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 301 DP - 2023 Jan 30 TI - Wutou decoction attenuates the synovial inflammation of collagen-induced arthritis rats via regulating macrophage M1/M2 type polarization. PG - 115802 LID - S0378-8741(22)00841-8 [pii] LID - 10.1016/j.jep.2022.115802 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Thousands of years of clinical practice in the treatment of joint-related diseases support the efficacy and safety of Wutou decoction (WTD). Nevertheless, the lack of pharmacological evidence and unclear mechanisms make it difficult for WTD to become a recognized complementary therapy for the treatment of rheumatoid arthritis (RA). AIM OF THE STUDY: This study aimed to investigate the effect of WTD against synovial inflammation in RA and whether this effect depends on the regulation of macrophage polarization. MATERIALS AND METHODS: Sprague-Dawley rats were used to establish the collagen-induced arthritis (CIA) model. WTD with low and high doses was administered for 45 days. RAW264.7 cells were stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4 to polarize M1 and M2 macrophages, which were pre-treated with WTD extract for 4 h. The anti-arthritic and anti-inflammatory effects of WTD were studied using arthritis score, histopathological staining, immunostaining, and enzyme-linked immunosorbent assay (ELISA). The polarization state of RAW264.7 cells and related pro/anti-inflammatory cytokines was detected by ELISA, reverse transcription quantitative polymerase chain reaction and western blotting. Western blotting and immunofluorescence were used to investigate the effect of WTD on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and peroxisome proliferator-activated receptors gamma (PPARgamma) activation both in vivo and in vitro. RESULTS: WTD significantly reduced the arthritis score and the pathological damage of the knee joint and decreased the expression of tumor necrosis factor alpha (TNF-alpha), IL-6 in serum, TNF-alpha, IL-1beta, monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-3 (MMP3) in the knee synovium. WTD inhibited M1 type polarization and promoted M2 type polarization, both in vitro and in vivo, and reduced the expression of pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines. Experiments showed that WTD inhibited the phosphorylation of NF-kappaB and downstream p38 in the synovium of CIA rats and LPS-induced M1 type polarized RAW264.7 cells. In addition, PPARgamma expression in the synovium of CIA rats was mainly located in the cytoplasm, and WTD treatment increased the nuclear translocation of PPARgamma, which was further verified in RAW264.7 cells. CONCLUSIONS: NF-kappaB and PPARgamma regulating M1 and M2 macrophage polarization and subsequent secretion of pro-inflammatory and anti-inflammatory cytokines are the underlying mechanisms of WTD that ameliorate RA synovial inflammation. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Lin, Weiji AU - Lin W AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Shen, Pan AU - Shen P AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Huang, Ying AU - Huang Y AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Han, Liang AU - Han L AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Ba, Xin AU - Ba X AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Huang, Yao AU - Huang Y AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Yan, Jiahui AU - Yan J AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Li, Tingting AU - Li T AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Xu, Lijun AU - Xu L AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Qin, Kai AU - Qin K AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Chen, Zhe AU - Chen Z AD - Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Tu, Shenghao AU - Tu S AD - Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: shtu@tjh.tjmu.edu.cn. LA - eng PT - Journal Article DEP - 20221006 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Cytokines) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (PPAR gamma) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - Rats MH - Anti-Inflammatory Agents MH - *Arthritis, Experimental/chemically induced/drug therapy/metabolism MH - *Arthritis, Rheumatoid/drug therapy MH - Cytokines/metabolism MH - Inflammation/drug therapy/metabolism MH - Lipopolysaccharides/toxicity/metabolism MH - Macrophages MH - NF-kappa B/metabolism MH - PPAR gamma/metabolism MH - Rats, Sprague-Dawley MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Macrophage polarization OT - NF-kappaB OT - PPARgamma OT - Rheumatoid arthritis OT - Synovial inflammation OT - Wutou decoction COIS- Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/10/10 06:00 MHDA- 2022/11/09 06:00 CRDT- 2022/10/09 19:25 PHST- 2022/07/02 00:00 [received] PHST- 2022/10/02 00:00 [revised] PHST- 2022/10/03 00:00 [accepted] PHST- 2022/10/10 06:00 [pubmed] PHST- 2022/11/09 06:00 [medline] PHST- 2022/10/09 19:25 [entrez] AID - S0378-8741(22)00841-8 [pii] AID - 10.1016/j.jep.2022.115802 [doi] PST - ppublish SO - J Ethnopharmacol. 2023 Jan 30;301:115802. doi: 10.1016/j.jep.2022.115802. Epub 2022 Oct 6.