Sphingosine 1-phosphate is a harbinger of S. aureus invasion and activates host defense in epithelial barriers

Abstract Background Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator generated in the skin when cell membrane or barrier components are damaged. S1P regulates diverse cell activities via S1P receptors (S1PR). Keratinocytes express S1PR1–5. Although it is known that S1PRs control keratinocyte differentiation, apoptosis and wound healing, S1PR functions in keratinocyte infections are not fully elucidated. We hypothesized that S1P and S1PR-axis in keratinocytes works as a biosensor for bacterial invasion. Methods The expression of S1PRs were studied by immunofluorescence and qPCR. Cytokine transcription and secretion were detected by qPCR and ELISA, respectively. siRNA and S1PR2 antagonist, JTE013, were used to test the different S1PR functions. The S1P synthesis was tested by ATP depletion assay and ELISA. Results We found a high epidermal S1PR1 and 2 expressions in human impetigo skin. In vitro, in normal human epidermal keratinocytes (NHEK), S. aureus bacterial supernatant not only induced S1P production but also increased S1PR2 transcription and TNFα, IL36γ, 6 and 8 transcriptions, confirming our in vivo observation. S1P directly increased NHEK IL36γ, TNFα and IL8 expression, but not IL6. In both, S1P and S. aureus bacterial supernatant treated NHEK, S1PR1 knock down reduced IL36γ, TNFα and IL8 transcription, while S1PR2 antagonist, JTE013, blocked their protein secretion. Conclusions We proved that, during infections, keratinocytes communicate the infection by sensing S1P release and respond to it using receptors S1PR1 and 2, releasing pro-inflammatory cytokines.