How lipid mediators promote the resolution of inflammatory skin disease

皮肤是环境和身体内部之间的重要屏障，因此它是大量免疫细胞的家园，准备对入侵的病原体做出反应。然而，这些细胞必须对无害的环境物质和共生微生物保持耐受性。因此，必须严格调节皮肤免疫细胞的活性，以防止不适当的激活和随后的炎症。近年来研究表明，这种调节不是被动的，而是通过细胞表面受体、细胞间相互作用和调节分子的分泌等调节机制来积极维持的。这些调节机制的失调导致慢性炎症，如慢性炎症性皮肤病、牛皮癣和特应性皮炎（湿疹）。虽然已经研究了蛋白质参与炎症的主动调节，但脂质介质的参与仍然是一个相对未开发的研究领域。尽管皮肤是富含油脂的组织。本项目将分析在炎症反应的诱导、高峰和消退过程中存在于皮肤中的生物活性脂质介质，以识别参与调节炎症的信号脂质。这些脂质调节炎症的机制将通过体外和体内免疫细胞活性测定来确定，并且将检查操纵这些脂质抑制炎症的潜力。该项目将提供关键技术培训，如炎症性疾病（牛皮癣和特应性皮炎）的临床前模型、流式细胞术、细胞培养和免疫检测、ELISA、QPCR和质谱脂质组学分析。本项目将确定生物活性脂类对免疫细胞活性的新调控。这些发现将为治疗牛皮癣和特应性皮炎的新治疗策略铺平道路，这两种疾病是高度流行的炎症性皮肤病，目前尚无治愈方法。这些调节性脂质介质也可能在影响皮肤以外组织的炎症性疾病中失调，因此这项研究可能对我们对炎症性疾病的理解产生广泛的影响。

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.