<i>Staphylococcus aureus</i> biofilm elicits the expansion, activation and polarization of myeloid-derived suppressor cells <i>in vivo</i> and <i>in vitro</i>

<div><p><i>Staphylococcus aureus</i> (<i>S</i>. <i>aureus</i>) is one of the most common causes of biofilm infections in periprosthetic joint infections (PJIs). Accumulating evidence has shown that the immunosuppressive environment established by <i>S</i>. <i>aureus</i> biofilm infection in PJIs involves the presence of myeloid-derived suppressor cells (MDSCs) and M2-macrophages. Due to the diversity of MDSCs, little is known about whether <i>S</i>. <i>aureus</i> biofilm preferentially expands specific MDSC subsets or whether MDSCs can further differentiate into M2-macrophages during <i>S</i>. <i>aureus</i> biofilm infection. Here, we show that in agreement with the results from an established rat PJI model, <i>S</i>. <i>aureus</i> biofilm cocultured with freshly isolated bone marrow cells (BMCs) <i>in vitro</i> significantly increases the proportions of MDSCs, total macrophages and M2-macrophages. Interestingly, we find that treatment of the BMCs <i>in vitro</i> with <i>S</i>. <i>aureus</i> biofilm preferentially promotes the expansion of monocytic MDSCs but not granulocytic MDSCs. Biofilm treatment also substantially enhances the overall MDSC immunosuppressive activity in addition to the MDSC expansion <i>in vitro</i>. Importantly, we provide evidence that <i>S</i>. <i>aureus</i> biofilm is capable of further stimulating the conversion of monocytic MDSCs into M2-macrophages <i>in vitro</i> and <i>in vivo</i>. Collectively, our studies reveal a direct link between MDSCs and M2-macrophages occurring in <i>S</i>. <i>aureus</i>-associated PJIs.</p>