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

金黄色葡萄球菌 巨噬细胞 骨髓 癌症研究 免疫系统 化学 体内 骨髓炎 免疫学 微生物学 细胞生物学 生物 体外 生物化学 遗传学 细菌 生物技术
作者
Masahiko JIN,Xiaohu Wu,Jin Hu,Yijie Chen,Bingsheng Yang,Chubin Cheng,Mankai Yang,Xianrong Zhang
出处
期刊:PLOS Pathogens [Public Library of Science]
卷期号:20 (8): e1012437-e1012437
标识
DOI:10.1371/journal.ppat.1012437
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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