Department of Nephrology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang 330008, China.
Clin Immunol. 2023 Jun;251:109279. doi: 10.1016/j.clim.2023.109279. Epub 2023 Mar 8.
M1-like macrophages have been reported to play critical roles in acute kidney injury (AKI). Here, we elucidated the role of ubiquitin-specific protease 25 (USP25) in M1-like macrophages polarization and AKI. High USP25 expression was correlated with a decline in renal function in patients with acute kidney tubular injury and in mice with AKI. In contrast, USP25 knockout reduced M1-like macrophage infiltration, suppressed M1-like polarization, and improved AKI in mice, indicating that USP25 was necessary for M1-like polarization and proinflammatory response. Immunoprecipitation assay and liquid chromatography-tandem mass spectrometry showed that the M2 isoform of pyruvate kinase, muscle (PKM2) was a target substrate of USP25. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated the USP25 regulated aerobic glycolysis and lactate production during M1-like polarization via PKM2. Further analysis showed that the USP25-PKM2-aerobic glycolysis axis positively regulated M1-like polarization and exacerbated AKI in mice, providing potential therapeutic targets for AKI treatment.
M1 样巨噬细胞被报道在急性肾损伤（AKI）中发挥关键作用。在这里，我们阐明了泛素特异性蛋白酶 25（USP25）在 M1 样巨噬细胞极化和 AKI 中的作用。高表达 USP25 与急性肾小管损伤患者肾功能下降和 AKI 小鼠的肾功能下降相关。相反，USP25 敲除减少了 M1 样巨噬细胞浸润，抑制了 M1 样极化，并改善了 AKI 小鼠的预后，表明 USP25 是 M1 样极化和促炎反应所必需的。免疫沉淀和液相色谱-串联质谱分析表明，丙酮酸激酶 M2 同工型（PKM2）是 USP25 的靶标底物。京都基因与基因组百科全书通路分析表明，USP25 通过 PKM2 调节 M1 样极化期间的有氧糖酵解和乳酸生成。进一步分析表明，USP25-PKM2-有氧糖酵解轴正向调节 M1 样极化并加重 AKI 小鼠的病情，为 AKI 治疗提供了潜在的治疗靶点。
