Mitochondrial transfer to granulocytic myeloid-derived suppressor cells augments immunosuppressive activity [scRNA-seq]
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 explored whether G-MDSC activity could be modulated by increasing mitochondrial abundance using a co-culture paradigm with macrophages as a mitochondrial donor. Macrophages transferred mitochondria directly to G-MDSCs via tunneling nanotubes, which enhanced G-MDSC respiration as reflected by increased basal, maximal, and spare respiratory capacity. Augmenting mitochondrial abundance in G-MDSCs enhanced T cell suppressive activity concomitant with decreased TNF and IL-6 production. Adoptive transfer of macrophages in a mouse model of S. aureus prosthetic joint infection revealed mitochondrial transfer to G-MDSCs in vivo that enhanced their suppressive activity, leading to increased bacterial burden, which was reversed when mitochondrial DNA-depleted macrophages were introduced. Mitochondrial transfer in vivo was also demonstrated using transgenic mice where macrophage mitochondria were tagged with GFP. These findings support that G-MDSCs can exploit mitochondria to augment their anti-inflammatory properties in response to S. aureus biofilm. Overall design: At day 3 post-infection, untreated and EtBr-treated macrophages were adoptively transferred into mice with Staphylococcus aureus prosthetic joint infection. Phosphate-buffered saline (PBS) was administered to both wild-type and interferon gamma knockout (IFNG KO) mice. Twenty-four hours following adoptive transfer, infected tissue was harvested, and single-cell suspensions were prepared. Live CD45? cells were isolated by fluorescence-activated cell sorting (FACS) and subjected to single-cell RNA sequencing analysis.