Wang Rongrong, Wu Depei, Dai Jianfeng, Shen Jiaqi, Rong Jianjie, Chen Zixing, Jiao Yang, Qi Xiaofei
Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215006, PR China; National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Suzhou 215006, P R China; Institute of Blood and Marrow Transplantation, Suzhou 215006, PR China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215006, PR China; State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215000, PR China.
Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215006, PR China; National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Suzhou 215006, P R China; Institute of Blood and Marrow Transplantation, Suzhou 215006, PR China; State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215000, PR China.
Pharmacol Res. 2023 Mar;189:106707. doi: 10.1016/j.phrs.2023.106707. Epub 2023 Feb 21.
Acute graft-versus-host disease (aGvHD) is considered a result of "cytokine storm." Targeted therapeutic interventions on cytokines via ubiquitination regulatory pathways may provide a potential approach for aGvHD treatment. Ubiquitin-specific peptidase 11 (USP11) has been reported to play key roles in a variety of physiopathological processes by regulating the stability and function of several vital protein molecules. However, its role in aGvHD remains unclear. In this study, we identified USP11 was associated with aGvHD in patients. In the aGvHD mouse model, the colon and liver were more seriously affected in recipient mice who received USP11 wt bone marrow (BM) cells and eased after the donor was treated with a USP11 inhibitor or received USP11 ko BM cells. In mouse models, IL-6 was identified as a major effecter in accelerating aGvHD induced by USP11. In the cell model, IL-6 mRNA transcript was affected by USP11. In addition, USP11 also inhibited IL-6 degradation by affecting IL-6 ubiquitination. Furthermore, the positive correlation between USP11 and IL-6 was confirmed in the GvHD patients' samples. Collectively, all results indicated that USP11 played a critical role in the onset and progression of aGvHD. USP11 might be a potential target for aGvHD treatment.
急性移植物抗宿主病（aGvHD）被认为是“细胞因子风暴”的结果。通过泛素化调节途径对细胞因子进行靶向治疗干预可能为aGvHD的治疗提供一种潜在方法。据报道，泛素特异性蛋白酶11（USP11）通过调节几种重要蛋白质分子的稳定性和功能，在多种生理病理过程中发挥关键作用。然而，其在aGvHD中的作用仍不清楚。在本研究中，我们发现USP11与aGvHD患者有关。在aGvHD小鼠模型中，接受USP11野生型骨髓（BM）细胞的受体小鼠的结肠和肝脏受到的影响更严重，而在供体接受USP11抑制剂治疗或接受USP11基因敲除的BM细胞后，病情有所缓解。在小鼠模型中，白细胞介素-6（IL-6）被确定为加速USP11诱导的aGvHD的主要效应因子。在细胞模型中，IL-6信使核糖核酸转录本受USP11影响。此外，USP11还通过影响IL-6的泛素化抑制其降解。此外，在移植物抗宿主病患者样本中证实了USP11与IL-6之间的正相关。总体而言，所有结果表明USP11在aGvHD的发生和发展中起关键作用。USP11可能是aGvHD治疗的潜在靶点。
