The Affiliated Hospital of Nanjing University of Chinese Medicine, Department of Orthopedics, Nanjing, China.
Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Nanjing, Jiangsu Province, China.
Mediators Inflamm. 2019 Sep 8;2019:2165918. doi: 10.1155/2019/2165918. eCollection 2019.
Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1, IL-18, and HMGB1 and fibrosis markers TGF-, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.
越来越多的证据表明，不同组织中的巨噬细胞焦亡参与慢性无菌性炎症，并与组织纤维化有关。我们的最新研究还揭示了滑膜成纤维细胞焦亡在膝骨关节炎（KOA）发病和发展中的重要作用。在本研究中，我们旨在探讨滑膜巨噬细胞焦亡是否确实发生，以及这种细胞死亡形式是否与 KOA 的滑膜炎和纤维化有关。在 KOA 模型大鼠的滑膜组织中，我们观察到巨噬细胞耗竭导致 caspase1、NLRP3、ASC 和 GSDMD 的 mRNA 和蛋白表达均降低。此外，用特异性 caspase1 抑制剂 Ac-YVAD-CMK 处理的大鼠表现出较少的炎症反应和纤维化，不仅在促炎因子 IL-1、IL-18 和 HMGB1 以及纤维化标志物 TGF-β、PLOD2、COL1A1 和 TIMP1 的表达上，而且在 HE 染色、天狼星红染色和右膝关节的横径观察上也是如此。随后，我们在巨噬细胞中建立了 LPS+ATP 诱导的模型，模拟 KOA 的炎症环境并诱导巨噬细胞焦亡。转染 caspase1 siRNA 的巨噬细胞显示细胞死亡减少；同时，焦亡相关蛋白的相对表达也下调。此外，与转染 siRNA GSDMD 的巨噬细胞共培养后，滑膜成纤维细胞中的纤维化标志物水平显著降低。综上所述，滑膜巨噬细胞焦亡可能发生在 KOA 的病理过程中，抑制滑膜巨噬细胞焦亡可减轻 KOA 模型大鼠的滑膜炎和纤维化。
