UVB Induces Release of Bioactive Microvesicle Particles in Keratinocytes via Platelet-Activating Factor and Acid Sphingomyelinase

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Ultraviolet-B (UVB) radiation is only appreciably absorbed by the epidermis, yet induces both acute inflammation and delayed immunosuppression. These UVB effects are due to keratinocyte-derived factors. Our lab has previously determined that UVB induces the production of the lipid mediator, Platelet-activating factor (PAF), which is involved in mediating both acute pro-inflammatory and immunosuppressive UVB responses. PAF has been reported to contribute to acid sphingomyelinase (aSMase)-dependent generation of ceramide, a key regulator of the lipid releasing pathway of microvesicle particles (MVP), which are small membrane-derived vesicles released from the plasma membrane that can facilitate intercellular transport of bioactive molecules. We have previously reported that UVB induces MVP, but the mechanism of MVP production and MVP contents have not been characterized. In this study, we found that both UVB and the stable PAF-R agonist C-PAF generated MVP release in various skin-derived epithelial cell lines, human skin and WT mice skin. The PAF dependence of UVB-mediated MVP release was confirmed utilizing a PAF-R antagonist, PAF-R negative cell lines and PAFR -/- mice. Interestingly, we found that UVB induced MVP do not contain protein cytokines, but contain large amounts of PAF agonists that can stimulate PAF-R activation in recipient cells. A small-molecule inhibitor of aSMase effectively blocked CPAF- and UVB-mediated MVP release in epithelial cells, human skin ex vivo and murine skin in vivo, suggesting that aSMase is required for the UVB induced, PAF-R-dependent release of MVP. This study suggests that keratinocyte-derived MVP are involved in transferring PAF, likely by protecting this labile lipid from metabolism. The targeting of UVB-mediated MVP release could serve as a potential therapeutic target in mitigating UVB-induced acute inflammation and systemic immunosuppression.



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