How lipid mediators promote the resolution of inflammatory skin disease

The skin is a crucial barrier between the environment and the internal body, and as such it is home to a plethora of immune cells ready to respond to invading pathogens. However, these cells must remain tolerant to harmless environmental substances and commensal microbes. Therefore, the activity of skin immune cells must be tightly regulated to prevent inappropriate activation and subsequent inflammation. In recent years it has become clear that this regulation is not passive, but is actively maintained by regulatory mechanisms including cell surface receptors, cell-cell interactions and the secretion of regulatory molecules. Dysregulation of these regulatory mechanisms leads to chronic inflammation, such as that seen in the chronic inflammatory skin diseases, psoriasis and atopic dermatitis (eczema). Whilst the involvement of proteins in this active regulation of inflammation has been studied, the involvement of lipid mediators remains a relatively unexplored area of research. This is despite the skin being a highly lipid rich tissue. This project will profile the bioactive lipid mediators present in skin throughout the induction, peak and resolution of inflammatory responses, to identify signalling lipids involved in regulating inflammation. The mechanisms by which these lipids regulate inflammation will be determined using in vitro and in vivo immune cell activity assays, and the potential to manipulate these lipids to suppress inflammation will be examined. This project will provide training in key techniques such as pre-clinical models of inflammatory disease (psoriasis and atopic dermatitis), flow cytometry, cell culture and immunological assays, ELISA, QPCR and lipidomic analysis by mass spectrometry. This project will identify novel regulation of immune cell activity by bioactive lipids. These findings will pave the way for novel therapeutic strategies for the treatment of psoriasis and atopic dermatitis, which are highly prevalent inflammatory skin diseases, for which there is currently no cure. These regulatory lipid mediators may also be dysregulated in inflammatory diseases affecting tissues other than skin, so this research may have wide ranging impacts on our understanding of inflammatory disease.