PD-1/PD-L1 blockade is a potent adjuvant in treatment of Staphylococcus aureus osteomyelitis in mice

There is no effective therapy for implant-associated Staphylo-coccus aureus osteomyelitis, a devastating complication after orthopedic surgery. An immune-suppressive profile with up -regulated programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) was identified based on our transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis. PD-1/PD-L1 expression was up-regulated mainly in F4/80+ macrophages surrounding the abscess in S. aureus-infected bone. Mechanistically, PD-1/PD-L1 acti-vated mitophagy to suppress production of mitochondrial reactive oxygen species (ROS), suppressing the bactericidal function of macrophages. Using neutralizing antibodies for PD-L1 or PD-1, or knockout of PD-L1 adjuvant to genta-micin markedly reduced mitophagy in bone marrow F4/80+ cells, enhanced bacterial clearance in bone tissue and im-plants, and reduced bone destruction in mice. PD-1/PD-L1 expression was also increased in the bone marrow from indi-viduals with S. aureus osteomyelitis. These findings uncover a so far unknown function of PD-1/PD-L1-mediated mitophagy in suppressing the bactericidal function of bone marrow mac-rophages.