ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2024; 20(7):2555-2575. doi:10.7150/ijbs.93592 This issue Cite
Research Paper
Aberrant Expression of SLC7A11 Impairs the Antimicrobial Activities of Macrophages in Staphylococcus Aureus Osteomyelitis in Mice
1. Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
2. Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
3. Department of Trauma Orthopedics, Liuzhou People's Hospital, Liuzhou, Guangxi, China.
4. Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
* Bingsheng Yang and Wen Shu contributed equally to this work.
Abstract
Staphylococcus aureus (S. aureus) persistence in macrophages, potentially a reservoir for recurrence of chronic osteomyelitis, contributes to resistance and failure in treatment. As the mechanisms underlying survival of S. aureus in macrophages remain largely unknown, there has been no treatment approved. Here, in a mouse model of S. aureus osteomyelitis, we identified significantly up-regulated expression of SLC7A11 in both transcriptomes and translatomes of CD11b+F4/80+ macrophages, and validated a predominant distribution of SLC7A11 in F4/80+ cells around the S. aureus abscess. Importantly, pharmacological inhibition or genetic knockout of SLC7A11 promoted the bactericidal function of macrophages, reduced bacterial burden in the bone and improved bone structure in mice with S. aureus osteomyelitis. Mechanistically, aberrantly expressed SLC7A11 down-regulated the level of intracellular ROS and reduced lipid peroxidation, contributing to the impaired bactericidal function of macrophages. Interestingly, blocking SLC7A11 further activated expression of PD-L1 via the ROS-NF-κB axis, and a combination therapy of targeting both SLC7A11 and PD-L1 significantly enhanced the efficacy of clearing S. aureus in vitro and in vivo. Our findings suggest that targeting both SLC7A11 and PD-L1 is a promising therapeutic approach to reprogram the bactericidal function of macrophages and promote bacterial clearance in S. aureus osteomyelitis.
Keywords: Staphylococcus aureus, Osteomyelitis, SLC7A11, Macrophage, Lipid peroxidation, PD-L1
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