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EGFR-MEK1/2 cascade negatively regulates bactericidal function of bone marrow macrophages in mice with Staphylococcus
Mingchao Jin1,2, Xiaohu Wu1,2, Jin Hu1,2
1Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No.1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province, China.
Abstract:
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.
Insights
Staphylococcus aureus evades immune cells by activating the EGFR-MEK1/2 pathway, which impairs macrophage function. Inhibiting this pathway enhances bacterial clearance and bone healing in osteomyelitis.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Staphylococcus aureus survival within macrophages is key to immune evasion and osteomyelitis progression.
- Mechanisms of S. aureus intracellular immune evasion are not fully understood.
Purpose of the Study:
- To investigate the role of the MEK1/2 pathway in S. aureus osteomyelitis.
- To identify therapeutic targets for S. aureus osteomyelitis.
Main Methods:
- Mouse model of S. aureus osteomyelitis.
- Histological analysis of phosphorylated MEK1/2.
- Primary mouse bone marrow-derived macrophages (BMDMs) studies.
- Transcriptome analysis.
- In vitro and in vivo experiments with EGFR and MEK1/2 inhibitors.
Main Results:
- Inhibition of MEK1/2 reduced bacterial load and bone destruction in vivo.
- S. aureus activates the MEK1/2 pathway via EGFR signaling.
- EGFR-MEK1/2 cascade activation downregulates mitochondrial ROS by suppressing Chek2, impairing macrophage bactericidal function.
- EGFR inhibition restored Chek2 expression, enhanced bacterial clearance, and improved bone microstructure.
Conclusions:
- The EGFR-MEK1/2 cascade is crucial for host defense against S. aureus.
- S. aureus exploits this pathway to reduce mitochondrial ROS and suppress macrophage function.
- Targeting the EGFR-MEK1/2 pathway offers a potential therapeutic strategy for S. aureus osteomyelitis.
