Jeffrey B. Travers, M.D., Ph.D. (Advisor); Yanfang Chen, M.D., Ph.D. (Committee Member); Weiwen Long, Ph.D. (Committee Member); Michael P. Markey, Ph.D. (Committee Member); Ji C. Bihl, M.D., Ph.D. (Committee Member)
Doctor of Philosophy (PhD)
Ultraviolet-B (UV-B) radiation is one of the most common environmental factors and is known to induce the production of bioactive agents that cause several diseases including skin cancer. UVB exposure stimulates the production of a phospholipid activator, platelet-activating factor (PAF), and its analogs in keratinocytes that activate the PAF receptor (PAF-R) resulting in acute inflammatory and delayed systematic immunosuppressive effects. However, as UVB only penetrates into the skin epidermal layer, the detailed mechanisms of how UVB exerts systematic effects remains unclear. Previously we found that UVB induces keratinocytes to release large numbers of microvesicle particles (MVPs). These small membrane-bound particles are released from cells via an acid sphingomyelinase dependent lipid pathway and able to stably transfer signal molecules from cell to cell. As PAF-R activation could regulate acid sphingomyelinase enzymatic activity, we assessed the releasing pathway of UVB-induced keratinocyte MVPs requires PAF-R activation and acid sphingomyelinase in keratinocyte cell lines in vitro, human skin explants ex vivo and mice skin in vivo. We identified the calcium-sensing receptor (CaSR) as a marker for the detection of keratinocyte-derived MVPs in skin blister fluids and blood plasma. The enhanced CaSR-positive MVPs in blood plasma indicating that UVB-induced keratinocyte MVPs travel systemically from the epidermis. We detected low levels of most pro-inflammatory cytokines but found PAF like lipids can be stably carried and transferred by these UVB induced MVPs. The MVP carried PAF like lipids activate PAF-R in target cells result in skin inflammation. Finally, we found that UVB does not generate systemic immunosuppression in mice lacking aSMase which is associated with blocked MVP release, revealing a potential mechanism that UVB mediated immunosuppression is due to MVP systematically transferring PAF-R agonistic lipids. Though MVP is the key transporter, blockage of MVP release could have potential therapeutic effects on the UVB-induced inflammation and immunosuppression.
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