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

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

  • Mol Ther. 2022 Sep 14;S1525-0016(22)00560-3. doi: 10.1016/j.ymthe.2022.09.006.
Kaiqun Li 1,  Yuhui Chen 1,  Yihuang Lin 1,  Guangyan Zhang 1,  Jianwen Su 1,  Xiaohu Wu 1,  Caiyu Cheng 1,  Yutian Wang 1,  Bin Yu 2,  Xianrong Zhang 3
Affiliations

Affiliations

  • 1 Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province 510515, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province 510515, China.
  • 2 Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province 510515, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province 510515, China. Electronic address: [email protected].
  • 3 Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province 510515, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province 510515, China. Electronic address: [email protected].
PMID: 36104974 DOI: 10.1016/j.ymthe.2022.09.006
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.

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