Neutrophil-intrinsic TNF receptor signaling orchestrates host defense against <i>Staphylococcus aureus</i>

Abstract

<i>Staphylococcus aureus</i> is the leading cause of skin and soft tissue infections and is a major health burden due to the emergence of antibiotic-resistant strains. To address the unmet need of alternative treatments to antibiotics, a better understanding of the protective immune mechanisms against <i>S. aureus</i> skin infection is warranted. Here, we report that tumor necrosis factor (TNF) promoted protection against <i>S. aureus</i> in the skin, which was mediated by bone marrow-derived immune cells. Furthermore, neutrophil-intrinsic TNF receptor (TNFR) signaling directed immunity against <i>S. aureus</i> skin infections. Mechanistically, TNFR1 promoted neutrophil recruitment to the skin, whereas TNFR2 prevented systemic bacterial dissemination and directed neutrophil antimicrobial functions. Treatment with a TNFR2 agonist showed therapeutic efficacy against <i>S. aureus</i> and <i>Pseudomonas aeruginosa</i> skin infections, which involved increased neutrophil extracellular trap formation. Our findings revealed nonredundant roles for TNFR1 and TNFR2 in neutrophils for immunity against <i>S. aureus</i> and can be therapeutically targeted for protection against bacterial skin infections.