Targeting HMGB1 by ethyl pyruvate ameliorates systemic lupus erythematosus and reverses the senescent phenotype of bone marrow-mesenchymal stem cells
Targeting HMGB1 by ethyl pyruvate ameliorates systemic lupus erythematosus and reverses the senescent phenotype of bone marrow-mesenchymal stem cells
复制标题
丙酮酸乙酯靶向 HMGB1 可改善系统性红斑狼疮并逆转骨髓间充质干细胞的衰老表型
DOI：
10.18632/aging.102052
复制
发表时间：
2019-07-15
期刊：
影响因子：
5.2
通讯作者：
Gu, Zhifeng
中科院分区：
文献类型：
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作者：
Ji, Juan;Fu, Ting;Gu, Zhifeng
系统性红斑狼疮（SLE）是一种累及多器官、多系统的慢性自身免疫性疾病。来自SLE患者的间充质干细胞（MSCs）表现出生长、衰老表型和免疫调节功能受损等缺陷。有研究表明炎症微环境与细胞衰老密切相关。本研究采用定量蛋白质组学方法检测SLE患者骨髓培养上清液中细胞因子水平，发现HMGB 1在SLE患者骨髓中的表达明显增加。衰老相关β-半乳糖苷酶（SA-β-gal）染色、F-肌动蛋白染色和流式细胞术检测细胞衰老。HMGB 1刺激正常骨髓间充质干细胞后，SA-β-gal阳性细胞比例增加，细胞骨架结构紊乱，TLR 4-NF-κB信号被激活。最后，丙酮酸乙酯（EP）（40 mg/kg和100 mg/kg，每周三次），一种高安全性的HMGB 1抑制剂，腹腔注射治疗MRL/lpr小鼠8周。我们证明，EP减轻狼疮性肾炎的临床方面和延长MRL/lpr小鼠的生存期。同时，EP逆转了MRL/lpr小鼠BM-MSCs的衰老表型。HMGB 1可能是治疗SLE的一个有效靶点，也可能是MSCs移植后复发的原因之一。
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs and systems. Mesenchymal stem cells (MSCs) from SLE patients have demonstrated defects such as impaired growth, senescence phenotype and immunomodulatory functions. Some studies have suggested the close connection between inflammation microenvironment and cellular senescence. In the current study, we detected cytokines levels in bone marrow supernatant by the quantitative proteomics analysis, and found the expression of HMGB1 was remarkably increased in bone marrow from SLE patients. Senescence associated-β-galactosidase (SA-β-gal) staining, F-actin staining and flow cytometry were used to detect the senescence of cells. After stimulation of HMGB1 in normal MSCs, the ratio of SA-β-gal positive in BM-MSCs was increased, the organization of cytoskeleton was disordered, and TLR4-NF-κB signaling was activated. Finally, Ethyl pyruvate (EP) (40 mg/kg and 100 mg/kg, three times a week), a high security HMGB1 inhibitor, was injected intraperitoneally to treat MRL/lpr mice for 8 weeks. We demonstrated that EP alleviated the clinical aspects of lupus nephritis and prolonged survival of MRL/lpr mice. In the meantime, EP reversed the senescent phenotype of BM-MSCs from MRL/lpr mice. HMGB1 could be a promising target in SLE patients, and might be one of the reasons of recurrence after MSCs transplantation.