Theaflavin-3,3’-Digallate Ameliorates Collagen-Induced Arthritis Through Regulation of Autophagy and Macrophage Polarization

Lei Zhang,1,* Wenming Li,1,* Zhenyang Hou,2,* Zhidong Wang,1,* Wei Zhang,1 Xiaolong Liang,1 Zerui Wu,1 Tianhao Wang,1 Xin Liu,1 Xiaole Peng,1 Xing Yang,3 Huilin Yang,1 Dechun Geng1 1Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Orthopaedics, Tengzhou City Center People’s Hospital, Tengzhou, People’s Republic of China; 3Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huilin Yang; Dechun Geng, Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Email suzhouspine@163.com; szgengdc@suda.edu.cnPurpose: Previous studies have presented that theaflavin-3,3’-digallate (TFDG), one of natural flavonoids, have protective effects on collagen-induced arthritis (CIA). Besides, it was reported that TFDG could affect inflammatory signaling pathways, like NF-κB, JNK, and so on, to ameliorate inflammation. However, the anti-inflammatory mechanisms mentioned above are common to natural flavonoid products including TFDG. Therefore, this study aimed to further investigate the other mechanisms of TFDG against CIA.Methods: DBA/1 mice (8– 10 weeks) were intravenously injected Freund’s Adjuvant (100μL) at the base of tail and intraperitoneally injected PBS or different dosage of TFDG (1 mg/kg or 10 mg/kg). Then the paw and knee tissues were collected to assess the severity of joint destruction. In vitro experiments, bone marrow macrophages (BMMs) were exposed to TNF-α (10ng/mL) with or without different concentrations of TFDG (0.1μmol/L or 1.0μmol/L). Besides, the targets of TFDG were predicted with docking software and were verified through experiment.Results: TFDG treatment could reduce M1 macrophage (pro-inflammatory) and inflammatory cytokines, such as IL-1, IL− 6 and TNF-α, ...