Mechanisms of augmented UVB immunosuppressive responses by polyaromatic hydrocarbons

点击翻译按钮获取中文摘要

Abstract Humans are subjected daily to multiple and often simultaneous environmental stressors. Yet the complex interaction of these agents remains an understudied area. Notably, ultraviolet radiation (UVR) has profound effects on the skin and generates systemic consequences from fever to immunosuppression to vitamin D production. The ability of UVR to act as both immunosuppressant and mutagen allows this environmental agent to become a complete carcinogen and is the cause for non-melanoma skin cancer and melanoma. Besides, environmental pollutants, polycyclic aromatic hydrocarbons (PAH) are ubiquitous and exert immunomodulatory as well as pro-carcinogenic effects, in great part via acting as agonists for the aryl hydrocarbon receptor (AHR). However, there is a significant knowledge gap of interactions between UVR and pollutants. In particular, as UVB only penetrates the epidermis, a major question in photobiology is how UVB-treated skin sends systemic signals. Recent studies have indicated that small membrane-bound vesicles known as microvesicle particles (MVP) released from cells in response to various stressors can act as potent signaling agents due to their ability to carry nuclear and cytoplasmic components. We have demonstrated that UVB (not UVA) generates MVP release from epithelial cells and skin, which could provide a potential mechanism for UVB-mediated systemic signaling. Our group and others have shown that UVB (not UVA) generates high levels of the lipid mediator Platelet-activating factor (PAF) produced enzymatically and oxidized PAF agonists produced non-enzymatically via reactive oxygen species (ROS). Recent studies using PAFR-expressing/null cell lines and pharmacologic/genetic inhibition of ROS, and the enzyme acid sphingomyelinase (aSMase) have implicated the involvement of the PAF-receptor (PAFR) signaling resulting in aSMase activation in UVB generated MVP (UVB-MVP). We provide evidence that UVB-MVP carry bioactive PAF agonists, which we hypothesize mediate the delayed immunosuppressive effects of UVB. Importantly, we discovered that the PAH Benzo[a]pyrene (BaP) interaction with UVB releases high levels of UVB-MVP and generate increased levels of PAF agonists. Two aims are planned to test the hypothesis that BaP+UVR (UVA vs UVB) results in a synergistic production of ROS that generate PAF and UVR-MVP resulting in enhanced systemic immunosuppression in an AHR-independent manner. Aim 1 will use in vitro cell lines, ex vivo skin explants and in vivo murine genetic and pharmacologic models to determine the mechanisms of BaP augmentation of UVB-MVP and PAF generation as well as define PAFR role in BaP synergy with UVR using a simulated solar light (SSL) source that emits both UVA and UVB fluences. Aim 2 will define the roles of enhanced UVB-MVP generation by BaP and the involvement of Tregs and cytokines, including IL-10 and TGFβ in delayed immunosuppressive effects. Successful completion of this project will (i) define a novel mechanism by which a PAH pollutant can augment UVR-induced effects; and ii) address an important question in photobiology as to how a keratinocyte-specific stimulus can generate systemic signaling effects.