Yan Bing, Li Yi, Liu Yiding, Zhang Yuying, Liu Sha, Wang Fu, Gao Lu
School of Stomatology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian, 116044, P.R. China.
Technology Innovation Center of Immune and Oral Development & Regeneration, Dalian Medical University, Dalian, 116044, China.
J Transl Med. 2025 Aug 28;23(1):969. doi: 10.1186/s12967-025-07003-2.
BACKGROUND: Macrophage immunomodulation has emerged as a novel intervention and therapeutic strategy for temporomandibular joint osteoarthritis (TMJOA), potentially serving as a key approach for reducing synovial inflammation and promoting cartilage repair. The soluble epoxide hydrolase inhibitor (sEHi), TPPU, has shown potential therapeutic effects against inflammatory diseases and osteogenesis by elevating endogenous Epoxyeicosatrienoic acids (EETs). However, it remains largely unknown whether TPPU can reduce inflammation and cartilage degradation in the TMJOA. METHODS: In vivo, the effects of TPPU on articular cartilage and synovial tissue pathology were assessed using H&E, Masson, Safranin-O/Fast Green staining and immunohistochemistry in a mouse model of TMJOA induced by unilateral anterior crossbite (UAC). RNA-seq and Western Blot was employed to investigate the key signal pathway of TPPU on M1 macrophage polarization. Subsequently, a co-culture system of macrophages and ATDC5 chondrocytes was established, and the influence of TPPU-treated macrophages on chondrogenesis was evaluated through Alcian Blue staining and RT-qPCR. RESULTS: In vivo, we observed that in UAC-induced TMJOA mice, TPPU significantly reduced the infiltration of inflammatory cells in the synovium and the positive expression of inflammatory factors TNF-α and IL-1β. It also mitigated the degradation of cartilage matrix and increased the positive expression of chondrogenic markers SOX9 and COL II. In vitro experiments revealed that TPPU inhibited the polarization of M1 macrophages, reduced inflammatory responses, and subsequently increased the expression of chondrogenic markers (SOX9 and COLII) in chondrocytes. RNA-seq data indicated that the NF-κB/IL-17 pathway as a putative target following TPPU treatment in macrophages. Further experiments confirmed that the addition of TPPU to macrophages inhibited the reduction in chondrogenesis induced by IL-17 and NF-κB agonists in the co-cultured cells. CONCLUSIONS: Our study elucidates a novel role of TPPU in inhibiting M1 macrophage polarization and modulating inflammatory immune responses via the EETs/NF-κB/IL-17 axis, thereby inhibiting cartilage damage in TMJOA.
背景：巨噬细胞免疫调节已成为颞下颌关节骨关节炎（TMJOA）的一种新型干预和治疗策略，可能是减轻滑膜炎症和促进软骨修复的关键方法。可溶性环氧化物水解酶抑制剂（sEHi）TPPU已显示出通过提高内源性环氧二十碳三烯酸（EETs）对炎症性疾病和成骨的潜在治疗作用。然而，TPPU是否能减轻TMJOA中的炎症和软骨降解在很大程度上仍不清楚。 方法：在体内，使用苏木精-伊红（H&E）、马松（Masson）、番红O/固绿染色和免疫组织化学，在单侧前牙反合（UAC）诱导的TMJOA小鼠模型中评估TPPU对关节软骨和滑膜组织病理学的影响。采用RNA测序（RNA-seq）和蛋白质免疫印迹法研究TPPU对M1巨噬细胞极化的关键信号通路。随后，建立巨噬细胞与ATDC5软骨细胞的共培养系统，通过阿尔新蓝染色和实时定量聚合酶链反应（RT-qPCR）评估经TPPU处理的巨噬细胞对软骨生成的影响。 结果：在体内，我们观察到在UAC诱导的TMJOA小鼠中，TPPU显著减少了滑膜中炎性细胞的浸润以及炎性因子肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的阳性表达。它还减轻了软骨基质的降解，并增加了软骨生成标志物性别决定区Y框蛋白9（SOX9）和II型胶原蛋白（COL II）的阳性表达。体外实验表明，TPPU抑制M1巨噬细胞的极化，减少炎症反应，并随后增加软骨细胞中软骨生成标志物（SOX9和COLII）的表达。RNA-seq数据表明，核因子κB（NF-κB）/白细胞介素-17（IL-17）通路是TPPU处理巨噬细胞后的一个假定靶点。进一步的实验证实，向巨噬细胞中添加TPPU可抑制共培养细胞中IL-17和NF-κB激动剂诱导的软骨生成减少。 结论：我们的研究阐明了TPPU通过EETs/NF-κB/IL-17轴在抑制M1巨噬细胞极化和调节炎性免疫反应中的新作用，从而抑制TMJOA中的软骨损伤。
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