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

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.