Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization

  • Int Immunopharmacol. 2023 Dec;125(Pt B):111175. doi: 10.1016/j.intimp.2023.111175.
Chenyang Lu  1 ,  Rui-Juan Cheng  2 ,  Qiuping Zhang  2 ,  Yidan Hu  2 ,  Yaoyu Pu  2 ,  Ji Wen  2 ,  Yutong Zhong  2 ,  Zhigang Tang  2 ,  Liang Wu  2 ,  Shixiong Wei  3 ,  Pei-Suen Tsou  4 ,  David A Fox  4 ,  Shasha Li  5 ,  Yubin Luo  6 ,  Yi Liu  7
Affiliations
  • 1. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Division of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
  • 2. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, NO. 1 Shuai Fu Yuan, Wang Fu Jing Street, Beijing 100730, China.
  • 4. Division of Rheumatology, Department of Internal Medicine and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, USA.
  • 5. Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China. Electronic address: [email protected].
  • 6. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 7. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 37976601 DOI: 10.1016/j.intimp.2023.111175
Abstract

Objective: Cepharanthine (CEP) is a drug candidate for tumor, viral Infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood.

Methods: CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis. M1 macrophages were induced from THP-1 cells or mouse bone marrow-derived macrophages with LPS and IFN-γ. Bulk RNA-seq was performed on macrophage undergoing M1-polarizatioin. Western blotting was applied to determine pathways involved in monocyte chemotaxis and polarization. Glycolysis metabolites were measured by chemiluminescence while glycolytic Enzymes were examined by quantitative PCR.

Results: We found CEP significantly ameliorated synovial inflammation and joint destruction of CIA mice. It downregulated TNF-α levels in serum and in joints. The number of M1 macrophages were reduced in CEP-treated mice. In vitro, CEP inhibited monocyte chemotaxis to MCP-1 by downregulating CCR2 and reducing ERK1/2 signaling. Additionally, CEP suppressed M1 polarization of macrophages induced by LPS and IFN-γ. Genes involved in IFN-γ signaling, IL-6-JAK/STAT3 signaling, glycolysis, and Oxidative Phosphorylation process were downregulated by CEP. Several Enzymes critically involved in glycolytic metabolism were suppressed by CEP, which resulted in reduced citrate in M1-polarizing macrophages. The inhibitory effect of CEP on macrophage polarization might be attributed to the blockage of TLRs-MyD88/IRAK4-IRF5 signaling pathway together with suppression of overactivated glycolytic metabolism in M1-polarizing macrophages.

Conclusion: CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.

Keywords
Cepharanthine; Glycolytic metabolism; Macrophage polarization; Monocyte; Rheumatoid arthritis.
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