Toll-like receptor-2 and interleukin-1 signaling in keratinocytes during Staphylococcus aureus infections (46.9)

Abstract

Abstract Staphylococcus aureus is a significant human pathogen. Subcutaneous infections in mice trigger neutrophil recruitment in an IL-1β, but not IL-1α, dependent manner. Since S. aureus can colonize the skin we explored the role keratinocytes play as first responders to bacterial challenges. In mice, topical application of IL-1, S. aureus or the bacterial cell wall components lipoteichoic acid (LTA) and peptidoglycan (PGN) triggered neutrophil recruitment to the skin surface. In human tissue culture models IL-1α and IL-1β increased mRNA and protein production of the neutrophil chemotactic CXCL1, CXCL2 and IL-8. S. aureus, LTA and PGN induced similar expression profiles in a TLR2 dependent manner. The S. aureus activated chemokine production was preceded by significant IL-1α and IL-1β secretion. Expression of IL-1α was significantly higher than that of IL-1β. IL-1RI neutralization experiments revealed that S. aureus derived LTA and PGN induced chemokine expression requires IL-1RI signaling. Surprisingly, we further found that LTA and PGN initiated chemokine secretion is dependent upon endocrine IL-1α, but not IL-1β, signaling. Our data demonstrate that the innate immune response of keratinocytes is regulated differently than those of subcutaneous tissues. A multifaceted IL-1 scheme involving IL-1α in the skin and IL-1β in underlying tissues may represent a fail-safe system, which protects the host against genetic variation and immune evasion mechanisms developed by pathogens.