title: Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus.
abstract: 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.
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China.
authors.forename: Zhanchuan
authors.initials: Z
authors.lastname: Ma
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Li
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yu
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China.
authors.forename: Zhong-Gao
authors.initials: ZG
authors.lastname: Xu
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China. yihuanfa@jlu.edu.cn yy2324@columbia.edu.
authors.forename: Huanfa
authors.initials: H
authors.lastname: Yi
authors.affiliation: The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China. Department of Medicine, Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. yihuanfa@jlu.edu.cn yy2324@columbia.edu.
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Yang
mesh_terms: D000818:Animals; D001119:Arginase / Q000097:blood / Q000378:metabolism*; D002454:Cell Differentiation; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D018655:Lymphocyte Count; D016513:Mice, SCID; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000473:pathology*; D011507:Proteinuria / Q000097:blood / Q000150:complications / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; C574619:ARG1 protein, human; D001119:Arginase