Myeloid Specific Ablation of SHIP1 Boosts ex vivo Expansion and Regulatory Function of Myeloid-Derived Suppressor Cells in Inflammatory Arthritis

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population and the immunosuppressive function of MDSCs has been well established in tumor microenvironment. Recent studies show that adoptive transfer of MDSCs can ameliorate collagen-induced inflammatory arthritis (CIA), a mouse model of human rheumatoid arthritis (RA). Src homology 2 domain- containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was previously shown to regulate MDSC differentiation. In this study, we aimed to generate immunosuppressive MDSCs from mouse bone marrow (BM) through genetic modification combined with cytokine treatments, and to investigate the ability of these ex vivo induced BM-MDSCs to suppress inflammatory responses in the CIA mouse model of RA. We found that myeloid specific ablation of SHIP1 increased the ratio of MDSCs and enhanced their regulatory functions in cytokine induced BM culture. MDSCs from LysMcre:SHIP1flox/flox mouse BM culture demonstrated stronger inhibitory effect on T cell proliferation than those from control mouse BM. Ex vivo induced MDSCs from either control mice or mice with myeloid specific ablation of SHIP1 were administered to the CIA mice as a cell-based therapy to treat inflammatory arthritis. Adoptive transfer of either BM-MDSCs significantly reduced disease incidence and severity, but SHIP1 deficient BM-MDSCs exhibited even higher efficacy compared to wild-type BM-MDSCs. Furthermore, pharmacological inhibition of SHIP1 enhanced the expression of immune regulatory genes in BM-derived MDSCs, and adoptive transfer of these cells protected against CIA development. In conclusion, myeloid specific ablation of SHIP1 boosts ex vivo expansion and immune regulatory function of MDSCs in experimental inflammatory arthritis. These ex vivo generated BM-MDSCs may provide novel therapeutic opportunities for the treatment of RA and other inflammatory diseases.