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

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. Not all infections induce abscess formation, and tissue abscess typically result from pyrogenic bacterial infections. Here the authors use mouse models to assess bone infection with S. aureus and show that macrophage-derived amphiregulin promotes preadipocyte-to-myofibroblast transition via EGFR/mTOR signalling in peri-abscess microenvironments.