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

Bingsheng Yang, Jianwen Su, Jichang Wu, Zhongwen Wang, Jin Hu, Mankai Yang, Yihuang Lin, Mingchao Jin, Xiaochun Bai, Bin Yu and Xianrong Zhang ()
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Bingsheng Yang: Southern Medical University
Jianwen Su: Southern Medical University
Jichang Wu: Southern Medical University
Zhongwen Wang: Southern Medical University
Jin Hu: Southern Medical University
Mankai Yang: Southern Medical University
Yihuang Lin: Southern Medical University
Mingchao Jin: Southern Medical University
Xiaochun Bai: Southern Medical University
Bin Yu: Southern Medical University
Xianrong Zhang: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63551-7

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