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

Mol Ther. 2023 Jan 4;31(1):174-192. doi: 10.1016/j.ymthe.2022.09.006. Epub 2022 Sep 14.

Abstract

There is no effective therapy for implant-associated Staphylococcus 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 activated 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 gentamicin markedly reduced mitophagy in bone marrow F4/80+ cells, enhanced bacterial clearance in bone tissue and implants, and reduced bone destruction in mice. PD-1/PD-L1 expression was also increased in the bone marrow from individuals 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 macrophages.

Keywords: PD-1; PD-L1; Staphylococcus aureus; macrophage; osteomyelitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic
  • Animals
  • Antibodies* / therapeutic use
  • B7-H1 Antigen* / antagonists & inhibitors
  • B7-H1 Antigen* / genetics
  • Disease Models, Animal
  • Mice
  • Osteomyelitis* / metabolism
  • Osteomyelitis* / therapy
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / genetics
  • Staphylococcus aureus

Substances

  • Adjuvants, Immunologic
  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor
  • Antibodies