EGFR-MEK1/2 cascade negatively regulates bactericidal function of bone marrow macrophages in mice with Staphylococcus aureus osteomyelitis

被引:0
|
作者
Jin, Mingchao [1 ,2 ]
Wu, Xiaohu [1 ,2 ]
Hu, Jin [1 ,2 ]
Chen, Yijie [1 ,2 ]
Yang, Bingsheng [1 ,2 ]
Cheng, Chubin [1 ,2 ]
Yang, Mankai [1 ,2 ]
Zhang, Xianrong [1 ,2 ]
机构
[1] Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
[2] Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R China
基金
中国国家自然科学基金;
关键词
ACTIVATION; EXPRESSION;
D O I
10.1371/journal.ppat.1012437
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The ability of Staphylococcus aureus (S. aureus) to survive within macrophages is a critical strategy for immune evasion, contributing to the pathogenesis and progression of osteomyelitis. However, the underlying mechanisms remain poorly characterized. This study discovered that inhibiting the MEK1/2 pathway reduced bacterial load and mitigated bone destruction in a mouse model of S. aureus osteomyelitis. Histological staining revealed increased phosphorylated MEK1/2 levels in bone marrow macrophages surrounding abscess in the mouse model of S. aureus osteomyelitis. Activation of MEK1/2 pathway and its roles in impairing macrophage bactericidal function were confirmed in primary mouse bone marrow-derived macrophages (BMDMs). Transcriptome analysis and in vitro experiments demonstrated that S. aureus activates the MEK1/2 pathway through EGFR signaling. Moreover, we found that excessive activation of EGFR-MEK1/2 cascade downregulates mitochondrial reactive oxygen species (mtROS) levels by suppressing Chek2 expression, thereby impairing macrophage bactericidal function. Furthermore, pharmacological inhibition of EGFR signaling prevented upregulation of phosphorylated MEK1/2 and restored Chek2 expression in macrophages, significantly enhancing S. aureus clearance and improving bone microstructure in vivo. These findings highlight the critical role of the EGFR-MEK1/2 cascade in host immune defense against S. aureus, suggesting that S. aureus may reduce mtROS levels by overactivating the EGFR-MEK1/2 cascade, thereby suppressing macrophage bactericidal function. Therefore, combining EGFR-MEK1/2 pathway blockade with antibiotics could represent an effective therapeutic approach for the treatment of S. aureus osteomyelitis.
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页数:24
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