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Sinomenine ameliorates collagen-induced arthritis in mice by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling pathways

Acta Pharmacologica Sinica volume 44, pages 2504–2524 (2023)Cite this article

Abstract

Sinomenine (SIN) is an isoquinoline alkaloid isolated from Sinomenii Caulis, a traditional Chinese medicine used to treat rheumatoid arthritis (RA). Clinical trials have shown that SIN has comparable efficacy to methotrexate in treating patients with RA but with fewer adverse effects. In this study, we explored the anti-inflammatory effects and therapeutic targets of SIN in LPS-induced RAW264.7 cells and in collagen-induced arthritis (CIA) mice. LPS-induced RAW264.7 cells were pretreated with SIN (160, 320, 640 µM); and CIA mice were administered SIN (25, 50 and 100 mg·kg−1·d−1, i.p.) for 30 days. We first conducted a solvent-induced protein precipitation (SIP) assay in LPS-stimulated RAW264.7 cells and found positive evidence for the direct binding of SIN to guanylate-binding protein 5 (GBP5), which was supported by molecular simulation docking, proteomics, and binding affinity assays (KD = 3.486 µM). More importantly, SIN treatment markedly decreased the expression levels of proteins involved in the GBP5/P2X7R-NLRP3 pathways in both LPS-induced RAW264.7 cells and the paw tissue of CIA mice. Moreover, the levels of IL-1β, IL-18, IL-6, and TNF-α in both the supernatant of inflammatory cells and the serum of CIA mice were significantly reduced. This study illustrates a novel anti-inflammatory mechanism of SIN; SIN suppresses the activity of NLRP3-related pathways by competitively binding GBP5 and downregulating P2X7R protein expression, which ultimately contributes to the reduction of IL-1β and IL-18 production. The binding specificity of SIN to GBP5 and its inhibitory effect on GBP5 activity suggest that SIN has great potential as a specific GBP5 antagonist.

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Fig. 1: A SIP combined proteomic approach was used to screen for potential target proteins interacting with sinomenine in LPS-induced macrophages.
Fig. 2: A SIP combined proteomic approach was used to screen for potential target proteins interacting with sinomenine in LPS-induced macrophages.
Fig. 3: GBP5 protein was identified as a direct binding target of sinomenine.
Fig. 4: GBP5 protein was identified as a direct binding target of sinomenine.
Fig. 5: Sinomenine regulated the activation of the GBP5/P2X7R/NLRP3 pathway in LPS-induced RAW264.7 cells.
Fig. 6: Sinomenine regulated the activation of the GBP5/P2X7R-NLRP3 pathway in LPS-induced RAW264.7 cells.
Fig. 7: Sinomenine dose-dependently reduced the levels of proinflammatory factors, ROS, and Ca2+ in LPS-induced RAW264.7 cells.
Fig. 8: Sinomenine dose-dependently alleviated arthritis symptoms in CIA mice.
Fig. 9: Sinomenine reduced the levels of proinflammatory cytokines and alleviated both joint inflammation and bone destruction in CIA mice.
Fig. 10: Sinomenine inhibited the activity of the GBP5/P2X7R-NLRP3 pathway in the paw tissue of CIA mice.
Fig. 11: Sinomenine suppressed the activity of the GBP5/P2X7R-NLRP3 pathway in the paw tissue of CIA mice.
Fig. 12: Schematic diagram of the molecular mechanism of SIN.

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Acknowledgements

This research was supported by the Joint Research Fund for Overseas Chinese Scholars and Scholars in Hong Kong and Macao of National Natural Science Fund of China (Project No.: 81929003, 81628016), the 2020 Hunan Province Science and Technology Innovation Key Projects (Project No.: 2020SK1020), and the Sanming Project of Medicine in Shenzhen, Guangdong Province, China (Project No.: SZZYSM202111002).

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Authors and Affiliations

  1. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Juan-min Li, Hai-shan Deng, Wei-ting Wang, Pei-xun Wang, Zhong-qiu Liu, Lin-lin Lu & Hua Zhou

  2. State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Yun-da Yao, Jia-qin Hu, Liang Liu, Ying Xie & Hua Zhou

  3. Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, China

    Yun-da Yao & Jia-qin Hu

  4. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Yan Dong

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  9. Zhong-qiu Liu
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  10. Ying Xie
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  11. Lin-lin Lu
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  12. Hua Zhou
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Contributions

JML: Methodology, Data curation, Formal analysis, Investigation, Validation, and Visualization, Writing original draft. HSD: Methodology, Data curation, Formal analysis, Investigation, Validation, and Visualization. YDY: Methodology, Data curation, Formal analysis, Investigation, Validation, and Visualization. JQH: Methodology, Data curation, Formal analysis, Investigation, Validation, and Visualization. WTW: Methodology, Data curation, Formal analysis, Investigation, Validation, and Visualization. YD: Writing—review and editing. PXW: Writing—review and editing. Liang Liu: Writing—review and editing. ZQL: Writing—review and editing. YX: Conceptualization, Writing—review and editing. Lin-Lin Lu: Conceptualization, Resources and Supervision, Writing—review and editing. HZ: Conceptualization, Funding acquisition, Resources and Supervision, Writing—review and editing. All authors approved the final manuscript.

Corresponding authors

Correspondence to Zhong-qiu Liu, Ying Xie, Lin-lin Lu or Hua Zhou.

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Li, Jm., Deng, Hs., Yao, Yd. et al. Sinomenine ameliorates collagen-induced arthritis in mice by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling pathways. Acta Pharmacol Sin 44, 2504–2524 (2023). https://doi.org/10.1038/s41401-023-01124-4

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