Staphylococcus aureus β-hemolysin causes skin inflammation by acting as an agonist of epidermal growth factor receptor

Abstract

ABSTRACT Staphylococcus aureus is a common cause of inflammatory skin diseases, with one of its virulence factors, β-hemolysin (Hlb), known to promote skin colonization. However, its direct involvement in skin inflammation is unclear. In this study, we identified that Hlb activated the epidermal growth factor receptor (EGFR) to induce skin inflammation, through its sphingomyelinase activity. We found that Hlb promoted the activity of A Disintegrin And Metalloproteinase 17 (ADAM17), which cleaves EGFR ligands and triggers EGFR phosphorylation. Furthermore, we discovered that Hlb increased the exposure of phosphatidylserine on the cell membrane, thus enhancing ADAM17’s sheddase activity. To address this, we developed a neutralizing monoclonal antibody against Hlb, which effectively attenuated S. aureus-induced skin inflammation by blocking EGFR activation. Our findings provide critical insights into the role of Hlb in inflammatory skin diseases, shedding light on the endogenous signal pathway that triggers this process. IMPORTANCE Staphylococcus aureus is a Gram-positive opportunistic bacterium that is responsible for the majority of skin infections in humans. Our study provides important molecular insights into the pathogenesis of S. aureus skin infections and identifies a potential therapeutic target for the treatment of these infections. Our findings also indicate that β-hemolysin (Hlb) secreted by colonized S. aureus is a risk factor for epidermal growth factor receptor (EGFR)-related diseases by acting as an agonist of EGFR. The neutralized monoclonal antibody we have developed for the first time will provide a functional inhibitor of Hlb. This study provides important insights to better understand the relationship between the skin colonization of S. aureus and inflammatory skin diseases.

Keywords

• Staphylococcus aureus
• β-hemolysin
• EGFR
• ADAM17
• sphingomyelinase
• skin inflammation