Zhou Qi, Wang Wei, Yang Fujun, Wang Hao, Zhao Xiaodong, Zhou Yiqin, Fu Peiliang, Xu Yaozeng
Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Orthopedics, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China.
Front Bioeng Biotechnol. 2022 Mar 8;10:823933. doi: 10.3389/fbioe.2022.823933. eCollection 2022.
The communication between macrophages and tendon cells plays a critical role in regulating the tendon-healing process. However, the potential mechanisms through which macrophages can control peritendinous fibrosis are unknown. Our data showed a strong pro-inflammatory phenotype of macrophages after a mouse tendon-bone injury. Moreover, by using a small-molecule compound library, we identified an aldehyde dehydrogenase inhibitor, disulfiram (DSF), which can significantly promote the transition of macrophage from M1 to M2 phenotype and decrease macrophage pro-inflammatory phenotype. Mechanistically, DSF targets gasdermin D (GSDMD) to attenuate macrophage cell pyroptosis, interleukin-1β, and high mobility group box 1 protein release. These pro-inflammatory cytokines and damage-associated molecular patterns are essential for regulating tenocyte and fibroblast proliferation, migration, and fibrotic activity. Deficiency or inhibition of GSDMD significantly suppressed peritendinous fibrosis formation around the injured tendon and was accompanied by increased regenerated bone and fibrocartilage compared with the wild-type littermates. Collectively, these findings reveal a novel pathway of GSDMD-dependent macrophage cell pyroptosis in remodeling fibrogenesis in tendon-bone injury. Thus, GSDMD may represent a potential therapeutic target in tendon-bone healing.
巨噬细胞与肌腱细胞之间的通讯在调节肌腱愈合过程中起着关键作用。然而，巨噬细胞控制腱周纤维化的潜在机制尚不清楚。我们的数据显示，小鼠肌腱-骨损伤后巨噬细胞呈现出强烈的促炎表型。此外，通过使用小分子化合物库，我们鉴定出一种醛脱氢酶抑制剂双硫仑（DSF），它可以显著促进巨噬细胞从M1型向M2型表型转变，并降低巨噬细胞的促炎表型。从机制上讲，DSF靶向gasdermin D（GSDMD）以减轻巨噬细胞焦亡、白细胞介素-1β和高迁移率族蛋白B1的释放。这些促炎细胞因子和损伤相关分子模式对于调节肌腱细胞和成纤维细胞的增殖、迁移及纤维化活性至关重要。与野生型同窝小鼠相比，GSDMD的缺失或抑制显著抑制了损伤肌腱周围腱周纤维化的形成，并伴有再生骨和纤维软骨的增加。总体而言，这些发现揭示了一种在肌腱-骨损伤纤维形成重塑中依赖GSDMD的巨噬细胞焦亡新途径。因此，GSDMD可能是肌腱-骨愈合中的一个潜在治疗靶点。
