Yiguanjian decoction inhibits macrophage M1 polarization and attenuates hepatic fibrosis induced by CCl4/2-AAF

Ying Xu; Wen Xu; Wei Liu; Gaofeng Chen; Shili Jiang; Jiamei Chen; Xun Jian; Hua Zhang; Ping Liu; Yongping Mu

doi:10.1080/13880209.2021.1961820

Yiguanjian decoction inhibits macrophage M1 polarization and attenuates hepatic fibrosis induced by CCl₄/2-AAF

Pharm Biol. 2021 Dec;59(1):1150-1160. doi: 10.1080/13880209.2021.1961820.

Authors

Ying Xu^{1

2}, Wen Xu^{1

2}, Wei Liu^{1

2}, Gaofeng Chen^{1

2

3}, Shili Jiang^{1

2}, Jiamei Chen^{1

2

3}, Xun Jian^{1

2}, Hua Zhang^{1

2

3}, Ping Liu^{2

3

4}, Yongping Mu^{1

2

3}

Affiliations

¹ Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, Pudong District, China.
² Institute of Liver Diseases, Shanghai University of TCM, Shanghai, China.
³ Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai, China.
⁴ Clinical Key Laboratory of TCM of Shanghai, Shanghai, Pudong District, China.

Abstract

Context: Our previous studies indicated that Yiguanjian decoction (YGJ) has an anti-hepatic-fibrosis effect and could regulate macrophage status.

Objective: To elucidate the mechanism of YGJ in regulating macrophages.

Materials and methods: Liver cirrhosis was induced by CCl₄ for 12 weeks combined with 2-acetylaminofluorene (2-AAF) for the last 4 weeks in male Wistar rats. YGJ (3.56 mg/kg) orally administered in the last 4 weeks, and SORA (1 mg/kg) as control. In vitro, RAW264.7 cells were treated with lipopolysaccharides (LPSs) to induce macrophage polarization to the M1 phenotype, and they were co-cultured with WB-F344 cells and allocated to M group, YGJ group (2 μg/mL) and WIF-1 group (1 μg/mL) with untreated cells as control. The differentiation direction of WB-F344 cell line was observed in the presence or absence of YGJ. Pathology, fibrosis-related cytokines, macrophage polarization-related components, and Wnt signalling pathway components were detected.

Results: In vivo, the expression levels of α-SMA, Col (1), OV6, SOX9, EpCAM and M1 macrophage-related components (STAT1, IRF3, IRF5, IRF8, SOCS3) significantly decreased in the YGJ group compared with those in the 2-AAF/CCl₄ group (p < 0.01 or 0.05). In vitro, the expression levels of M1 macrophage-related components, including STAT1, NF-κB, IRF3, IRF5, and SOCS3, in RAW264.7 cells decreased significantly in the YGJ group compared with those in the M group (p < 0.05 or p < 0.01). The expression levels of Wnt3A, FZD5, LRP-5/-6, and β-catenin significantly increased in the YGJ group compared with those in the M group (p < 0.05 or p < 0.01). In addition, the expression levels of Wnt-4/-5A/-5B, and FZD2 significantly decreased in the YGJ group compared with those in the M group (p < 0.05 or p < 0.01).

Conclusion: This study suggests that the anti-cirrhosis effect of YGJ is associated with its ability to inhibit macrophage M1-polarization, which provides a scientific basis for the clinical application of YGJ.

Keywords: Liver cirrhosis; Wnt signalling pathway; hepatic progenitor cells.

MeSH terms

2-Acetylaminofluorene
Animals
Carbon Tetrachloride
Cell Line
Cytokines / metabolism
Drugs, Chinese Herbal / pharmacology*
Liver Cirrhosis, Experimental / drug therapy*
Macrophages / drug effects*
Macrophages / metabolism
Male
Mice
RAW 264.7 Cells
Rats
Rats, Inbred F344
Rats, Wistar
Wnt Signaling Pathway / drug effects

Substances

Cytokines
Drugs, Chinese Herbal
yiguanjian decoction
2-Acetylaminofluorene
Carbon Tetrachloride

Grants and funding

This study was supported by the National Natural Science Foundation of China [No.81874390, No. 81573948 and No. 82004162].