MDSCs enhance Th17 differentiation and disease progression through arginase-1 production in patients with systemic lupus erythematosus

Abstract

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. Although MDSCs are supposed to be immunosuppressive, previous studies have shown that these cells may also enhance Th17 responses via an IL-1-dependent mechanism in murine autoimmune models, such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). However, the role of MDSCs in the development of autoimmune responses in human remains largely unknown. Current study investigates this question in patients with systemic lupus erythematosus (SLE). We found that patients with active SLE (n=32) had a significant increase in HLA-DR−CD11b+CD33+ MDSCs, in the peripheral blood compared to healthy controls (HCs; n=25). The frequency of MDSCs was positively correlated with the level of serum arginase-1 (Arg-1) activity, 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 that is likely mediated by multiple mechanisms involving RORgt, RORa and mTOR. 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, and suggests that targeting MDSCs or Arg-1 may offer novel therapeutic strategies for the treatment of SLE and other Th17 cell-mediated autoimmune diseases.