CCL20/CCR6 signaling modulates disease severity during the establishment of <i>Staphylococcus aureus</i> osteomyelitis

<i>Staphylococcus aureus</i> is the most common pathogen in orthopedic infections, and hard-to-treat strains (methicillin-resistant <i>S. aureus</i>) cause >50% of these infections. Thus, there is an urgent need to develop immunotherapies to treat these life-threatening infections. The role of the CCL20/CCR6 chemokine signaling axis on <i>S. aureus</i> osteomyelitis is unknown. In our efforts to uncover its role, we reveal that osteoblasts and macrophages secrete CCL20 in response to infection, and mice lacking CCL20 or its monogamous receptor CCR6 are more susceptible to <i>S. aureus</i> osteomyelitis. Mechanistically, we observed that increased infection severity in the knockout mice is associated with decreased T cell recruitment and increased osteoclastogenesis at the bone infection site. Importantly, in a clinical pilot study, we observed that CCL20 can be a useful biomarker of osteomyelitis-induced septic death. Overall, our study highlights the crucial immunomodulatory role that the CCL20/CCR6 axis plays during osteomyelitis.