TNF receptors orchestrate differential neutrophil responses critical to immunity against Staphylococcus aureusskin infection

Abstract

Abstract As the leading cause of skin and soft tissue infections, Staphylococcus aureus is a major health burden and a continued threat to human health due to the emergence of antibiotic-resistance. Through this current study, we aimed to better characterize the protective immune mechanisms against S. aureus skin infection to identify novel targets for the development of host-directed immunotherapeutics as alternatives to antibiotics. Tumor necrosis factor (TNF) is a master regulatory cytokine whose inhibition is associated with the increased risk of S. aureus skin colonization and infection in humans. Despite the clinical implications, the contribution of TNF and its cognate receptors, TNFR1 and TNFR2, to immunity against S. aureus skin infection is unclear. Utilizing an in vivo mouse model of S. aureus intradermal infection, we determined that immune cell-derived TNF engages with both TNFR1 and TNFR2 to promote protection against S. aureus in the skin. Neutrophil-intrinsic TNFR1 and TNFR2 signaling directed differential antimicrobial mechanisms against S. aureus skin infections. Mechanistically, TNFR1 mediated neutrophil recruitment to the skin, whereas TNFR2 directed neutrophil activation (e.g.-NOX2 activation, ROS production, and PAD4-dependent neutrophil extracellular trap (NET) formation) and prevented systemic dissemination of skin infection. Collectively, our findings revealed non-redundant functions and cellular mechanisms mediated by TNFR1 and TNFR2 in neutrophils for immunity against S. aureus. This study was funded in part by grants R01AR073665 (NKA), R01AR069502 (NKA), R01AI111205 (NKA), and R01AI146177 (NKA) and from the United States National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and National Institute of Allergy and Infectious Diseases (NIAID).