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<p>The formation of <i>Staphylococcus aureus</i> (<i>S. aureus</i>) abscesses is a well-established determinant of persistent skeletal infections, yet the mechanisms underlying bacterial persistence remain elusive. Here, we demonstrate that bone marrow adiponectin-positive (<i>Adipoq</i><sup><i>+</i></sup>) precursors are mobilized to surround <i>S. aureus</i> abscesses and undergo myofibroblast differentiation. This phenotypic transition induces vascular constriction, thereby impairing local perfusion and impeding effective bacterial clearance. Mechanistically, macrophage-derived amphiregulin (AREG) activates EGFR signaling on <i>Adipoq</i><sup><i>+</i></sup> cells, triggering the mTOR/YAP pathway to drive their myofibroblast transition. Importantly, genetic ablation of <i>Adipoq</i><sup><i>+</i></sup> cells, cell-specific deletion of the AREG/EGFR axis, or pharmacological inhibition of EGFR/mTOR signaling effectively alleviates fibrosis, restores vascular perfusion and antibiotic delivery, and promotes bacterial eradication from abscesses. Our findings implicate a macrophage-<i>Adipoq</i><sup><i>+</i></sup> cell regulatory axis that sustains <i>S. aureus</i> persistence in osteomyelitis and identify therapeutic targeting of this axis as a strategy to enhance antibiotic efficacy against <i>S. aureus</i> skeletal infections.</p>

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Macrophage-derived amphiregulin induces myofibroblast transition in adipogenic lineage precursors near Staphylococcus aureus abscess in bone marrow

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Bingsheng Yang,
  • Jianwen Su,
  • Jichang Wu,
  • Zhongwen Wang,
  • Jin Hu,
  • Mankai Yang,
  • Yihuang Lin,
  • Mingchao Jin,
  • Xiaochun Bai,
  • Bin Yu,
  • Xianrong Zhang

摘要

The formation of Staphylococcus aureus (S. aureus) abscesses is a well-established determinant of persistent skeletal infections, yet the mechanisms underlying bacterial persistence remain elusive. Here, we demonstrate that bone marrow adiponectin-positive (Adipoq+) precursors are mobilized to surround S. aureus abscesses and undergo myofibroblast differentiation. This phenotypic transition induces vascular constriction, thereby impairing local perfusion and impeding effective bacterial clearance. Mechanistically, macrophage-derived amphiregulin (AREG) activates EGFR signaling on Adipoq+ cells, triggering the mTOR/YAP pathway to drive their myofibroblast transition. Importantly, genetic ablation of Adipoq+ cells, cell-specific deletion of the AREG/EGFR axis, or pharmacological inhibition of EGFR/mTOR signaling effectively alleviates fibrosis, restores vascular perfusion and antibiotic delivery, and promotes bacterial eradication from abscesses. Our findings implicate a macrophage-Adipoq+ cell regulatory axis that sustains S. aureus persistence in osteomyelitis and identify therapeutic targeting of this axis as a strategy to enhance antibiotic efficacy against S. aureus skeletal infections.