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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Osteomyelitis*/microbiology ; Osteomyelitis*/immunology ; Osteomyelitis*/metabolism ; Staphylococcal Infections*/immunology ; Staphylococcal Infections*/metabolism ; Staphylococcal Infections*/microbiology ; Staphylococcus aureus*/immunology ; ErbB Receptors*/metabolism ; Macrophages*/immunology ; Macrophages*/metabolism ; Macrophages*/microbiology ; MAP Kinase Kinase 1*/metabolism; Animals ; Mice ; MAP Kinase Kinase 2/metabolism ; MAP Kinase Signaling System/physiology ; Mice, Inbred C57BL ; Disease Models, Animal ; Signal Transduction

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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Jin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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EC 2.7.10.1 (ErbB Receptors)
EC 2.7.12.2 (MAP Kinase Kinase 1)
EC 2.7.10.1 (EGFR protein, mouse)
EC 2.7.12.2 (MAP Kinase Kinase 2)
EC 2.7.12.2 (Map2k1 protein, mouse)
EC 2.7.12.2 (Map2k2 protein, mouse)

Date Created: 20240805 Date Completed: 20240815 Latest Revision: 20240819

20240820

PMC11326603

10.1371/journal.ppat.1012437

39102432