Wu Xiaohu, Guan Xin, Cheng Chubin, Deng Zhantao, Li Zeng, Ma Yuanchen, Xie Yanjie, Zheng Qiujian
Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Orthopedics, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Mol Med. 2025 May 29;31(1):211. doi: 10.1186/s10020-025-01274-7.
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.
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.
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.
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.
巨噬细胞作为抵御微生物入侵的一线防御者，却通过尚不明确的免疫抑制机制，反常地成为金黄色葡萄球菌（金葡菌）引发骨髓炎发病机制中的帮凶。
在本研究中，我们建立了用MEK1抑制剂治疗的金葡菌植入相关股骨感染模型，并评估了骨破坏程度和细菌载量。随后，我们研究了MEK1抑制剂处理后，金葡菌激活的骨髓来源巨噬细胞（BMDM）中线粒体活性氧（mtROS）水平、线粒体自噬活性、吞噬杀伤能力及CHEK2线粒体转位的变化。最后，进行了涉及不同抑制剂组合的体内实验，以评估线粒体自噬水平及治疗骨髓炎的潜力。
MEK1的药理学抑制显著减轻了骨髓炎小鼠模型中的骨降解和病原体负担，表明其具有治疗潜力。对BMDM的研究表明，阻断MEK1-ERK1/2轴通过抑制线粒体自噬增加mtROS水平，直接将代谢重编程与杀菌活性增加联系起来。从机制上讲，MEK1-ERK1/2途径的失活恢复了CHEK2的表达，促进其从细胞核转位到线粒体，通过抑制线粒体自噬来恢复mtROS水平。重要的是，体内研究证实，MEK1-ERK1/2-CHEK2轴对于控制金葡菌感染期间线粒体自噬依赖性骨病理和细菌持续存在至关重要。
我们发现了一个自我放大的致病环，其中金葡菌利用巨噬细胞MEK1过度激活ERK1/2，导致CHEK2表达受抑制。这一过程导致过度的线粒体自噬和mtROS水平降低，损害杀菌功能并导致不受控制的溶骨性破坏。这些发现将MEK1重新定义为代谢-免疫检查点，并突出了其在骨髓炎中可药物靶向的脆弱性。
