Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation

Highlights

• MDSC consists of polymorphonuclear and mononuclear subsets and its ratio varies during the development of CIA.

• Depletion of MDSC at the early stage of disease ameliorates joint destruction.

• MDSCs are proinflammatory during the early stages of CIA development.

• This proinflammatory effect is due to the induction of Th17 differentiation via MDSC-derived IL-1β.

Abstract

Myeloid-derived suppressor cells (MDSC) and Th17 cells were found to expand in collagen-induced arthritis (CIA) significantly. Two subsets of MDSC, polymorphonuclear (PMN) and mononuclear (MO), were detected and their ratios varied during the development of CIA. The depletion of MDSC in vivo resulted in suppression of T-cell proliferation and decreased IL-17A and IL-1β production. The adoptive transfer of MDSC restored the severity of arthritis and Th17 cell differentiation. The depletion of MDSCs on day 35 resulted in arthritis amelioration without reaching a significant difference. Furthermore, MDSCs from CIA mice had higher production of IL-1β and promoted Th17 cell differentiation. The expansion of MDSCs in the peripheral blood of rheumatoid arthritis (RA) patients was in correlation with increased Th17 cells and disease activity DAS28. These results support the hypothesis that MDSC may play a significant proinflammatory role in the pathogenesis of CIA and RA by inducing Th17 development in an IL-1β-dependent manner.

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology that affects small diarthrodial joints with chronic inflammation, cartilage destruction, and bone erosions [1]. Recent advances in therapy have dramatically reduced morbidity for RA. However, there is still a significant number of RA patients who are resistant to the current therapy and to further reduction in disability [1], [2].

Th17 cell is a CD4⁺ T-cell subset characterized by the production of inflammatory cytokine IL-17 [3], [4], and they have been shown to be involved in many human autoimmune diseases, including RA, psoriasis, and multiple sclerosis [5]. The production of IL-17 has been observed to be elevated in RA murine models as well as in RA patients [6], [7]. In collagen-induced arthritis (CIA), IL-17 correlates with joint damage [8]. IL-17-deficient mice are protected from CIA [9], and treatment with a neutralizing IL-17 antibody reduces joint inflammation, cartilage destruction, and bone erosion in CIA [10].

In recent years, myeloid-derived suppressor cells (MDSCs) have attracted considerable attention in the context of tumor because of its suppressive effect in tumor immunity [11], [12]. MDSCs were originally described as a heterogeneous population of immature cells with immunosuppressive functions in tumor-bearing hosts. The immunosuppressive mechanisms of MDSC are complex [13]. In mice, MDSCs are characterized by the expression of cell surface makers CD11b and Gr-1. Two functionally subsets have been described, Ly6G⁺Ly6C^lowpolymorphonuclear (PMN) and Ly6G⁻Ly6C^highmononuclear (MO) cells [14], [15], [16]. In humans, MDSCs lack the characteristic markers and have been identified as CD14⁺HLA-DR^−/low [17], [18], or Lin⁻CD11b⁺CD33⁺HLA-DR⁻ [19]. In addition to their role in tumor immunology, MDSCs were shown to regulate immune response in animal models of autoimmune diseases [17], [20], infectious diseases [21] and trauma [22].

Although the immunosuppressive function of MDSC in tumor has been well established [12], their regulation in autoimmune diseases has not yet been well defined. In experimental autoimmune encephalomyelitis (EAE), MDSCs have been found in some studies to increase dramatically in the spleen and to exert an immunosuppressive role [20], [23]. These cells were found to ameliorate demyelination and delay disease onset after in vivo transfer through inhibiting Th1 and Th17 cells [20]. In other studies, MDSCs were found to be recruited into the central nervous system and play a pathogenic role [24], [25]. In addition, MDSCs were found to contribute to the pathogenesis of EAE by driving Th17 cells differentiation [26]. In proteoglycan-induced arthritis, MDSCs from synovial fluid of the affected joints, in contrast to splenic MDSCs, limited the expansion of auto-reactive T cells in vitro [27]. However, their specific roles in other experimental models and in RA patients, particularly the in vivo function, remain to be elucidated.

From this brief discussion, it is clear that Th17 cells and MDSCs play significant pathogenic roles in autoimmune disorders, but the relationship between these two types of immune cell remains to be elucidated. In this study, we examined the pathogenic role of MDSC in CIA and their role in the differentiation of Th17 cells.