Research ArticleAutoimmunity

Arginase-1–dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus

Science Translational Medicine  23 Mar 2016:
Vol. 8, Issue 331, pp. 331ra40
DOI: 10.1126/scitranslmed.aae0482

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Looping in myeloid-derived suppressor cells

Suppressing misdirected or overactive immune responses is a critical approach for treating autoimmune diseases such as system lupus erythematosus (SLE). However, Wu et al. now report that one immunosuppressive cell type, myeloid-derived suppressor cells (MDSCs), actually contribute to SLE pathogenesis. There are increased numbers of MDSCs in patients with SLE, and these cells produce elevated levels of arginase-1 compared with MDSCs from healthy controls. What’s more, these arginase-1–producing MDSCs contribute to the development of TH17 cells, which are pathogenic in SLE. These data suggest that targeting MDSCs may be a therapeutic strategy for TH17-mediated autoimmune diseases.

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-DRCD11b+CD33+ MDSCs, including both CD14+CD66b monocytic and CD14CD66b+ 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.

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