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Background <p>Macrophages, which serve as the frontline defenders against microbial invasion, paradoxically become accomplices in <i>Staphylococcus aureus</i> (<i>S. aureus</i>)-driven osteomyelitis pathogenesis through poorly defined immunosuppressive mechanisms.</p> Methods <p>In this study, we established an <i>S. aureus</i> implant-associated femoral infection model treated with MEK1 inhibitors and evaluated the degree of bone destruction and the bacterial load. We subsequently investigated changes in mitochondrial ROS (mtROS) levels, mitophagy activity, phagocytic–killing ability, and CHEK2 mitochondrial translocation in <i>S. aureus</i>-activated bone marrow-derived macrophages (BMDMs) following MEK1 inhibitor treatment. Finally, in vivo experiments involving different inhibitor combinations were conducted to assess mitophagy levels and the therapeutic potential for treating osteomyelitis.</p> Results <p>Pharmacological inhibition of MEK1 significantly attenuated bone degradation and the pathogen burden in murine models of osteomyelitis, indicating its therapeutic potential. Investigations using BMDMs revealed that blockade of the MEK1-ERK1/2 axis increases mtROS levels by suppressing mitophagy, directly linking metabolic reprogramming to increased bactericidal activity. Mechanistically, inactivation of the MEK1-ERK1/2 pathway restores CHEK2 expression, facilitating its translocation from the nucleus to mitochondria to restore mtROS levels by inhibiting mitophagy. Importantly, in vivo studies confirmed that the MEK1-ERK1/2-CHEK2 axis is pivotal for controlling mitophagy-dependent bone pathology and bacterial persistence during <i>S. aureus</i> infection.</p> Conclusions <p>We identified a self-amplifying pathogenic loop in which <i>S. aureus</i> exploits macrophage MEK1 to hyperactivate ERK1/2, leading to the suppression of CHEK2 expression. This process results in excessive mitophagy and decreased mtROS levels, which impair the bactericidal function and enable uncontrolled osteolytic destruction. These findings redefine MEK1 as a metabolic–immune checkpoint and highlight its druggable vulnerability in osteomyelitis.</p>

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Activation of the MEK1-CHK2 axis in macrophages by Staphylococcus aureus promotes mitophagy, resulting in a reduction in bactericidal efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月29日

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  • Xiaohu Wu,
  • Xin Guan,
  • Chubin Cheng,
  • Zhantao Deng,
  • Zeng Li,
  • Yuanchen Ma,
  • Yanjie Xie,
  • Qiujian Zheng

摘要

Background

Macrophages, which serve as the frontline defenders against microbial invasion, paradoxically become accomplices in Staphylococcus aureus (S. aureus)-driven osteomyelitis pathogenesis through poorly defined immunosuppressive mechanisms.

Methods

In this study, we established an S. aureus implant-associated femoral infection model treated with MEK1 inhibitors and evaluated the degree of bone destruction and the bacterial load. We subsequently investigated changes in mitochondrial ROS (mtROS) levels, mitophagy activity, phagocytic–killing ability, and CHEK2 mitochondrial translocation in S. aureus-activated bone marrow-derived macrophages (BMDMs) following MEK1 inhibitor treatment. Finally, in vivo experiments involving different inhibitor combinations were conducted to assess mitophagy levels and the therapeutic potential for treating osteomyelitis.

Results

Pharmacological inhibition of MEK1 significantly attenuated bone degradation and the pathogen burden in murine models of osteomyelitis, indicating its therapeutic potential. Investigations using BMDMs revealed that blockade of the MEK1-ERK1/2 axis increases mtROS levels by suppressing mitophagy, directly linking metabolic reprogramming to increased bactericidal activity. Mechanistically, inactivation of the MEK1-ERK1/2 pathway restores CHEK2 expression, facilitating its translocation from the nucleus to mitochondria to restore mtROS levels by inhibiting mitophagy. Importantly, in vivo studies confirmed that the MEK1-ERK1/2-CHEK2 axis is pivotal for controlling mitophagy-dependent bone pathology and bacterial persistence during S. aureus infection.

Conclusions

We identified a self-amplifying pathogenic loop in which S. aureus exploits macrophage MEK1 to hyperactivate ERK1/2, leading to the suppression of CHEK2 expression. This process results in excessive mitophagy and decreased mtROS levels, which impair the bactericidal function and enable uncontrolled osteolytic destruction. These findings redefine MEK1 as a metabolic–immune checkpoint and highlight its druggable vulnerability in osteomyelitis.