EGFR-MEK1/2 cascade negatively regulates bactericidal function of bone marrow macrophages in mice with Staphylococcus aureus osteomyelitis
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作者:
Jin, Mingchao
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Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Jin, Mingchao
[1
,2
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Wu, Xiaohu
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机构:
Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Wu, Xiaohu
[1
,2
]
Hu, Jin
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机构:
Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Hu, Jin
[1
,2
]
Chen, Yijie
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Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Chen, Yijie
[1
,2
]
Yang, Bingsheng
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Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Yang, Bingsheng
[1
,2
]
Cheng, Chubin
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Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Cheng, Chubin
[1
,2
]
Yang, Mankai
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Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Yang, Mankai
[1
,2
]
Zhang, Xianrong
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Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou, Peoples R ChinaSouthern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed & Traumatol, 1838 North Guangzhou Ave, Guangzhou, Guangdong, Peoples R China
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
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.
机构:
Chinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Translat Med Res Ctr, Med Innovat Res Div, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, Beijing 100048, Peoples R ChinaChinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
Liu, Shuang-Qing
Ren, Chao
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Chinese Peoples Liberat Army Gen Hosp, Translat Med Res Ctr, Med Innovat Res Div, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, Beijing 100048, Peoples R ChinaChinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
Ren, Chao
Yao, Ren-Qi
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Chinese Peoples Liberat Army Gen Hosp, Translat Med Res Ctr, Med Innovat Res Div, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, Beijing 100048, Peoples R China
Naval Med Univ, Dept Burn Surg, Affiliated Hosp 1, Shanghai 200433, Peoples R ChinaChinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
Yao, Ren-Qi
Wu, Yao
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机构:
Chinese Peoples Liberat Army Gen Hosp, Translat Med Res Ctr, Med Innovat Res Div, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, Beijing 100048, Peoples R ChinaChinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
Wu, Yao
Luan, Ying-Yi
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Chinese Peoples Liberat Army Gen Hosp, Translat Med Res Ctr, Med Innovat Res Div, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, Beijing 100048, Peoples R ChinaChinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
Luan, Ying-Yi
Dong, Ning
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Chinese Peoples Liberat Army Gen Hosp, Translat Med Res Ctr, Med Innovat Res Div, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, Beijing 100048, Peoples R ChinaChinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
Dong, Ning
Yao, Yong-Ming
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Chinese Peoples Liberat Army Gen Hosp, Translat Med Res Ctr, Med Innovat Res Div, Beijing 100048, Peoples R China
Chinese Peoples Liberat Army Gen Hosp, Med Ctr 4, Beijing 100048, Peoples R ChinaChinese Peoples Liberat Army Gen Hosp, Dept Emergency, Med Ctr 4, Beijing 100048, Peoples R China
机构:
Kunming Med Univ, Grad Sch, Kunming, Peoples R China
920th Hosp Joint Logist Support Force, Orthopaed Dept, 212 Daguan Rd, Kunming 650032, Peoples R ChinaKunming Med Univ, Grad Sch, Kunming, Peoples R China
Song, Muguo
Lv, Kehan
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Kunming Med Univ, Grad Sch, Kunming, Peoples R China
920th Hosp Joint Logist Support Force, Orthopaed Dept, 212 Daguan Rd, Kunming 650032, Peoples R ChinaKunming Med Univ, Grad Sch, Kunming, Peoples R China
Lv, Kehan
Xu, Zhi
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Kunming Med Univ, Grad Sch, Kunming, Peoples R China
920th Hosp Joint Logist Support Force, Orthopaed Dept, 212 Daguan Rd, Kunming 650032, Peoples R ChinaKunming Med Univ, Grad Sch, Kunming, Peoples R China
Xu, Zhi
Li, Junyi
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Kunming Med Univ, Grad Sch, Kunming, Peoples R China
920th Hosp Joint Logist Support Force, Orthopaed Dept, 212 Daguan Rd, Kunming 650032, Peoples R ChinaKunming Med Univ, Grad Sch, Kunming, Peoples R China
Li, Junyi
Sun, Jian
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机构:
Kunming Med Univ, Grad Sch, Kunming, Peoples R China
920th Hosp Joint Logist Support Force, Orthopaed Dept, 212 Daguan Rd, Kunming 650032, Peoples R ChinaKunming Med Univ, Grad Sch, Kunming, Peoples R China
Sun, Jian
Shi, Jian
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机构:
920th Hosp Joint Logist Support Force, Orthopaed Dept, 212 Daguan Rd, Kunming 650032, Peoples R ChinaKunming Med Univ, Grad Sch, Kunming, Peoples R China
Shi, Jian
Xu, Yongqing
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920th Hosp Joint Logist Support Force, Orthopaed Dept, 212 Daguan Rd, Kunming 650032, Peoples R ChinaKunming Med Univ, Grad Sch, Kunming, Peoples R China