Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.
Int J Biol Sci. 2024 Oct 21;20(14):5731-5746. doi: 10.7150/ijbs.99738. eCollection 2024.
Increasing evidence suggests that the mononuclear/macrophage system is vital in amplifying the inflammatory cascade in IgA Nephropathy (IgAN). However, the pathogenic mechanism of macrophages in IgAN and targeted treatment strategies still need to be explored. This study found that botanical triterpene celastrol (CLT) effectively alleviated renal lesions, M1-like macrophage infiltration, inflammatory factors production, and improved renal function in IgAN mice. We found that the renal macrophages of IgAN patients had high expression of ECM1, a crucial molecule involved in macrophage inflammatory polarization, positively correlated with the IgAN clinical severity. In murine macrophage Raw 264.7 cells, CLT inhibited macrophage M1-like polarization and the output of TNF-α and IL-6 by downregulating the ECM1/STAT5 pathway. Mechanistically, molecular docking, CESTA, and immunoprecipitation verified that CLT directly bound to ECM1 and increased the ubiquitination of ECM1. Collectively, these results illustrated that CLT inhibited proinflammatory macrophage in IgAN by directly targeting ECM1 to promote ubiquitination degradation of ECM1. Therefore, this study may provide a theoretical basis for exploring the pathogenesis of IgAN and identifying new perspectives for targeted therapy of IgAN.
越来越多的证据表明，单核/巨噬细胞系统在 IgA 肾病（IgAN）中放大炎症级联反应中起着至关重要的作用。然而，巨噬细胞在 IgAN 中的致病机制和靶向治疗策略仍有待探索。本研究发现，植物三萜化合物雷公藤红素（CLT）可有效减轻 IgAN 小鼠的肾脏病变、M1 样巨噬细胞浸润、炎症因子产生，并改善肾功能。我们发现，IgAN 患者的肾脏巨噬细胞中 ECM1 表达水平较高，ECM1 是参与巨噬细胞炎症极化的关键分子，与 IgAN 的临床严重程度呈正相关。在鼠巨噬细胞 Raw 264.7 细胞中，CLT 通过下调 ECM1/STAT5 通路抑制巨噬细胞 M1 样极化和 TNF-α 和 IL-6 的产生。从机制上讲，分子对接、CESTA 和免疫沉淀实验验证了 CLT 可直接与 ECM1 结合，并增加 ECM1 的泛素化。综上所述，这些结果表明，CLT 通过直接靶向 ECM1 抑制促炎型巨噬细胞，从而促进 ECM1 的泛素化降解。因此，本研究可能为探索 IgAN 的发病机制和寻找 IgAN 的靶向治疗新视角提供了理论依据。
