Generation and activity of oxidized lipid mediators in the skin.
Exposure of human keratinocytes or fibroblasts to long wave UV-radiation, which is the dominant UV component of sunlight, generates an impressive diversity of oxidized lipid species. These oxdized phospholipids are formed from unoxidized precursors that constitute cellular membranes, and several of the oxidized species can form after UV radiation in the absence of enzymes (Gruber, et al., JBC 2008). Together with Valery Bochkov at the Institute for Vascular Biology of the MUW we have developed a method that allowes us to monitor several hundred individual oxidized lipids simultaneously (Gruber, et al., JLR 2012) and to investigate their role in cellular stress and senescence.
The coordinated stress responses to environmental insults and their role in skin aging.
Environmental insults to the skin range from solar irradiation to microbial pathogens and dynamic responses by epidermal keratinocytes and dermal fibroblasts to cope with cellular damage. Autophagy is a mechanism initiated during cellular stress or starvation that results in lysosomal degradation of macromolecules and organelles to provide nutrients and metabolites that support cell survival. We found that autophagy is an important mechanism for epidermal KCs that suffered UV- and oxidized lipid stress to remove aggregated proteins and oxidized lipids themselves (Zhao, et al., JID 2013).
We also found that autophagy is thightly coordinated with an other stress response mechanism of the skin, the Nrf2 directed antioxidant response. The protection of epidermal KCs against exogenous or endogenous oxidant stress is orchestrated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a redox-sensitive transcription factor. Within the epidermis, Nrf2 provides both stress-inducible de novo synthesis of antioxidants and a permanent inside-out gradient of antioxidants that coincides with KC differentiation. UV irradiation and oxidized phospholipids induce Nrf2 activation (Gruber, et al. FASEB J. 2010), and when autophagy is inhibited the Nrf2 response is dramatically hyperinduced, resulting in overexpression of Nrf2 target genes (Zhao, et al., JID 2013).
Both, a reduced antioxidant response and increased deposition of protein aggregates and oxidized lipids are observed in cellular senescence but also in skin aging, so one major focus of our work is to investigate the role of the stress response pathways in intrinsic and extrinsic skin aging.