Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization

Chenyang Lu; Rui-Juan Cheng; Qiuping Zhang; Yidan Hu; Yaoyu Pu; Ji Wen; Yutong Zhong; Zhigang Tang; Liang Wu; Shixiong Wei; Pei-Suen Tsou; David A Fox; Shasha Li; Yubin Luo; Yi Liu

doi:10.1016/j.intimp.2023.111175

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. Epub 2023 Nov 16.

Authors

Chenyang Lu¹, Rui-Juan Cheng², Qiuping Zhang², Yidan Hu², Yaoyu Pu², Ji Wen², Yutong Zhong², Zhigang Tang², Liang Wu², Shixiong Wei³, Pei-Suen Tsou⁴, David A Fox⁴, Shasha Li⁵, Yubin Luo⁶, Yi Liu⁷

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: lishsh85@mail.sysu.edu.cn.
⁶ Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: luoyubin2016@163.com.
⁷ Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yiliu8999@wchscu.cn.

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.

MeSH terms

Animals
Arthritis, Experimental* / drug therapy
Arthritis, Rheumatoid* / drug therapy
Benzylisoquinolines* / pharmacology
Benzylisoquinolines* / therapeutic use
Inflammation
Lipopolysaccharides
Mice

Substances

cepharanthine
Lipopolysaccharides
Benzylisoquinolines