Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus.
Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus.
复制标题
系统性红斑狼疮中 MDSC 依赖精氨酸酶 1 促进 T(H)17 分化和疾病进展
DOI：
10.1126/scitranslmed.aae0482
复制
发表时间：
2016-03-23
影响因子：
17.1
通讯作者：
Yang YG
中科院分区：
文献类型：
--
作者：
Wu H;Zhen Y;Ma Z;Li H;Yu J;Xu ZG;Wang XY;Yi H;Yang YG
骨髓源性抑制细胞（MDSC）的扩增已在一些小鼠模型和自身免疫性疾病患者中得到证实，但MDSC在这一过程中的确切作用在很大程度上仍然未知。目前的研究调查了系统性红斑狼疮（SLE）患者的这一问题。与健康对照组（HC）相比，活动性SLE患者外周血中HLA-DR− CD 11b + CD 33 + MDSC（包括CD 14 + CD 66 b −单核细胞和CD 14 − CD 66 b+粒细胞MDSC）显著增加。SLE患者MDSC的发生率与血清精氨酸酶-1（Arg-1）活性、辅助性T细胞17（TH 17）反应水平和疾病严重程度呈正相关。一致地，与来自HC的MDSC相比，来自SLE患者的MDSC表现出显著升高的Arg-1产生，并且以Arg-1依赖性方式在体外促进TH 17分化的潜力增加。此外，在人源化SLE模型中，MDSC对于诱导TH 17应答和相关的肾损伤是必不可少的，并且MDSC的作用是Arg-1依赖性的。我们的数据提供了直接证据，证明MDSC在人类SLE中的致病作用。本研究还通过证实MDSC在TH 17细胞相关自身免疫的发展中的Arg-1依赖性作用提供了SLE发病的分子机制，并表明靶向MDSC或Arg-1可能为治疗SLE和其他TH 17细胞介导的自身免疫性疾病提供潜在的治疗策略。
Expansion of myeloid-derived suppressor cells (MDSCs) has been documented in some murine models and patients with autoimmune diseases, but the exact role of MDSCs in this process remains largely unknown. The current study investigates this question in patients with systemic lupus erythematosus (SLE). Patients with active SLE showed a significant increase in HLA-DR−CD11b+CD33+ MDSCs, including both CD14+CD66b− monocytic and CD14−CD66b+ granulocytic MDSCs, in the peripheral blood compared to healthy controls (HCs). The frequency of MDSCs was positively correlated with the levels of serum arginase-1 (Arg-1) activity, T helper 17 (TH17) responses, and disease severity in SLE patients. Consistently, in comparison with MDSCs from HCs, MDSCs from SLE patients exhibited significantly elevated Arg-1 production and increased potential to promote TH17 differentiation in vitro in an Arg-1–dependent manner. Moreover, in a humanized SLE model, MDSCs were essential for the induction of TH17 responses and the associated renal injuries, and the effect of MDSCs was Arg-1–dependent. Our data provide direct evidence demonstrating a pathogenic role for MDSCs in human SLE. This study also provides a molecular mechanism of the pathogenesis of SLE by demonstrating an Arg-1–dependent effect of MDSCs in the development of TH17 cell–associated autoimmunity, and suggests that targeting MDSCs or Arg-1 may offer potential therapeutic strategies for the treatment of SLE and other TH17 cell–mediated autoimmune diseases.