TAS4464, a neddylation inhibitor, mitigates Staphylococcus aureus-induced periprosthetic joint infection by modulating immunosuppressive cell functions

Staphylococcus aureus (S. aureus) is a leading cause of biofilm-associated periprosthetic joint infections (PJIs), in part due to its ability to induce an immunosuppressive environment. Biofilm formation promotes the expansion of myeloid-derived suppressor cells (MDSCs) and M2 macrophages, which impair host immune responses and facilitate infection persistence. Targeting these immunosuppressive cells offers a promising therapeutic strategy for treating S. aureus biofilm-associated PJIs. Neddylation, a post-translational modification involving the conjugation of the ubiquitin-like protein NEDD8 to target proteins, regulates various cellular processes and may influence immune cell function during infection. Here, we investigated the role of neddylation in S. aureus biofilm-induced immunosuppression. We found that TAS4464, a selective neddylation inhibitor, markedly suppressed the expansion of MDSCs and M2 macrophages in bone marrow cells (BMCs) stimulated by S. aureus biofilm. TAS4464 also reduced the expression of inflammation-associated cytokines in these cells. Mechanistically, S. aureus biofilm upregulated key components of the neddylation pathway and markers of MDSCs and M2 macrophages in a dose-dependent manner; however, this upregulation is effectively counteracted by TAS4464. Furthermore, in a mouse model of PJI, TAS4464 treatment significantly reduced bone destruction and inflammation, which correlates with the inhibition of the neddylation pathway and a decrease in circulating MDSCs and M2 macrophages. These findings suggest that TAS4464 mitigates S. aureus biofilm-associated PJIs by disrupting the immunosuppressive microenvironment and highlight neddylation as a potential therapeutic target.