Theaflavin-3,3'-Digallate 通过调节自噬和巨噬细胞极化改善胶原诱导的关节炎,Journal of Inflammation Research

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Theaflavin-3,3'-Digallate 通过调节自噬和巨噬细胞极化改善胶原诱导的关节炎
Journal of Inflammation Research ( IF 4.2 ) Pub Date : 2023-01-10 , DOI: 10.2147/jir.s374802
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 Geng ₁

Affiliation

目的：先前的研究表明，茶黄素 3,3'-二没食子酸酯 (TFDG) 是一种天然黄酮类化合物，对胶原性关节炎 (CIA) 具有保护作用。此外，据报道TFDG可以影响炎症信号通路，如NF-κB、JNK等，从而改善炎症。然而，上述抗炎机制对于包括TFDG在内的天然类黄酮产品是常见的。因此，本研究旨在进一步研究 TFDG 对抗 CIA 的其他机制。
方法：DBA/1小鼠（8-10周龄）在尾根部静脉注射弗氏佐剂（100μL），腹腔注射PBS或不同剂量的TFDG（1mg/kg或10mg/kg）。然后收集爪子和膝盖组织以评估关节破坏的严重程度。在体外实验中，骨髓巨噬细胞 (BMM) 暴露于 TNF-α (10ng/mL)，有或没有不同浓度的 TFDG（0.1μmol/L 或 1.0μmol/L）。此外，TFDG的目标是用对接软件预测的，并通过实验进行了验证。
结果：TFDG 处理可以在体外和体内减少 M1 巨噬细胞（促炎）和炎性细胞因子，如 IL-1、IL-6 和 TNF-α。同时，TFDG 促进了 M2 巨噬细胞（或者激活的）极化。动物实验表明 TFDG 可改善关节破坏。为了研究这些机制，TFDG 的目标是通过生物信息学工具预测的。根据预测，我们假设 TFDG 可以与 BCL-2 共同作用，削弱 BCL-2 和 Beclin1 之间的相互作用。Beclin1 在自噬中起着核心作用，我们发现 BMMs 的自噬水平被 TFDG 恢复。此外，自噬抑制剂3-MA可减弱TFDG的治疗作用。
结论：TFDG 通过减轻炎症和通过控制自噬促进抗炎 M2 巨噬细胞极化来防止胶原诱导的关节炎。
图解摘要：

关键词：茶黄素 3,3'-二没食子酸酯、自噬、炎症、巨噬细胞极化、类风湿性关节炎

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

Purpose: 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, both in vitro and in vivo. At the same time, the M2 macrophage (alternatively activated) polarization was promoted by TFDG. Animal experiments showed TFDG ameliorated joint destructions. For investigating the mechanisms, the targets of TFDG were predicted by bioinformatics tools. According to predictions, we hypothesized that TFDG could act with BCL-2 to weaken the interaction between BCL-2 and Beclin1. Beclin1 plays a central role in autophagy, and we found that the autophagy level of BMMs was recovered by TFDG. Besides, 3-MA, an autophagy inhibitor, could attenuate the therapeutic effect of TFDG.
Conclusion: TFDG protected against collagen-induced arthritis by attenuating the inflammation and promoting anti-inflammatory M2 macrophage polarization through controlling autophagy.
Graphical Abstract:

Keywords: theaflavin-3,3’-digallate, autophagy, inflammation, macrophage polarization, rheumatoid arthritis

更新日期：2023-01-10

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