Mitochondrial transfer to granulocytic myeloid-derived suppressor cells augments immunosuppressive activity

The anti-inflammatory properties of granulocytic myeloid-derived suppressor cells (G-MDSCs) promote Staphylococcus aureus (S. aureus) biofilm persistence. Evidence suggests that G-MDSC activity is not only shaped by S. aureus products but also by intrinsic metabolic programs. This study explores whether G-MDSC activity can be modulated by increasing mitochondrial abundance using a co-culture paradigm with macrophages as a mitochondrial donor. Macrophages transfer mitochondria directly to G-MDSCs via tunneling nanotubes, enhancing G-MDSC respiration as reflected by increased basal, maximal, and spare respiratory capacity. Augmenting mitochondrial abundance in G-MDSCs enhances T cell suppressive activity and reduces TNF and IL-6 production. In a mouse model of S. aureus prosthetic joint infection, adoptively transferred macrophages deliver mitochondria to G-MDSCs, enhancing their suppressive activity and increasing bacterial burden, which is reversed when mitochondrial DNA depleted macrophages are introduced. These findings support that G-MDSCs exploit mitochondria to augment their anti-inflammatory properties in response to S. aureus biofilm.