Title : Platelet-activating factor-receptor pathway mediates solar radiation-induced extracellular vesicle release in human keratinocytes
Abstract:
Solar ultraviolet (UV) radiation is a major environmental toxicant that contributes to inflammation, immunosuppression, and carcinogenesis. Previous studies suggest that UVB-induced oxidative stress generates oxidized lipids with platelet-activating factor (PAF) agonistic activity, which act through the PAF- receptor (PAFR) to activate downstream signaling cascades, including acid sphingomyelinase (aSMase) enzyme. While UVB-induced oxidative stress stimulates the release of extracellular vesicles (EVs), the mechanisms of solar-simulated light (SSL), which represents the physiological source of solar radiation on the kinetics of cellular response and EVs are not clear. Given that EVs, including microvesicle particles (MVPs) and exosomes, are increasingly recognized as mediators of intercellular communication during environmental stress and considered as biomarkers of pathological stage, this study examined the role of PAFR signaling in SSL-induced EV release in human keratinocytes. Utilizing state-of-the art methodologies, our demonstrated that SSL exposure reduced the viability of epidermal keratinocytes in a dose- and time-dependent manner. SSL exposure also induced a significant dose-dependent increase in MVP and exosome release at various timepoints. Importantly, inhibition of PAFR significantly attenuated the SSL-mediated EV release, supporting a mechanistic role for PAFR in regulating this response. The findings that SSL inhibits cell viability and augments MVP and exosome release in a process blocked by PAFR and microvesicle inhibition, indicate that PAFR could be explored as a potential target for mitigating SSL-induced phototoxic skin response.
