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

There has been no effective therapy for implant-associated Staphylococcus aureus (S. aureus) osteomyelitis, a devastating complication following 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 (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 activated mitophagy to suppress production of mitochondrial ROS, thereby suppressing the bactericidal function of macrophages. Importantly, either anti-PD-1 or anti-PD-L1 or knock-out of PD-L1 adjuvant to gentamicin markedly reduced mitophagy in bone marrow F4/80 cells, enhances bacterial clearance in bone tissue and implants, and reduced bone destruction in mice. Excitingly, PD-1/PD-L1 expression was also increased in the bone marrow from patients with S. aureus osteomyelitis. These findings uncovered a hitherto unknown function of PD-1/PD-L1-mediated mitophagy in suppressing bactericidal function of bone marrow macrophages.