Fibroblasts resist Staphylococcus aureus on the skin surface by responding to interleukin-1 and recruiting neutrophils.

Staphylococcus aureus can cause serious infections, yet it can also reside on the skin without causing disease. This apparent paradox implies a strong host defense system, which prevents S. aureus from invading the dermis. In this study, we investigate how the skin detects and responds to superficial S. aureus exposure. Using unbiased transcriptomic, biochemical, and phosphoproteomic analyses, followed by targeted validation in human and mouse models, we found that fibroblast recognition of interleukin-1 is essential for immune response. Deletion or blockade of the interleukin-1 receptor type 1 (IL-1R1) in fibroblasts in vitro abolished keratinocyte-driven changes in gene expression and reduced chemokine production. Furthermore, the skin of mice lacking fibroblast IL-1R1 had fewer neutrophils and higher bacterial load after topical S. aureus application. These findings show that fibroblasts actively participate in innate immunity and highlight an IL-1R1-dependent keratinocyte-fibroblast-neutrophil axis of communication. Understanding this pathway provides insights into mechanisms that initiate neutrophil recruitment to the skin and may help develop new approaches to therapy.