Determining Monocyte and Macrophage Diversity in the Mucosal Immune System

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Macrophages are amongst the most abundance immune cell type in most healthy tissues of the body where they play key roles in regulating tissue development and maintaining tissue homeostasis. These cells are also an essential component of the innate immune system where they provide an important first line of defence against infection by phagocytosing and destroying pathogens. However, in some circumstances the dysregulation of these important macrophage function can contribute to a range of inflammatory diseases. Macrophages occupy many varied niches throughout the body and may convey distinct roles depending on these locations, such as provision of homeostatic support or immunosurveillance of body surfaces. How these highly varied characteristics and functions are imprinted in the macrophages or their precursor cells is poorly understood. Similarly, it is uncertain whether specific macrophage sub-types in one tissue location such as the lung, are also replicated in other mucosal tissues such as the intestine, nasal cavity etc. However, a range of genes have been identified that are required for the differentiation of certain macrophage subsets. For example, the nuclear receptor LXRa is essential for the development of macrophages in the marginal zone of the spleen. Studies from Dr. Bain's lab have shown how the transcription factor EGR2 plays an important role in the differentiation of alveolar macrophages in the lung. The highly conserved super-enhancer, FIRE, within the CSF1R gene is important for the development of macrophages in specific tissues including the embryo, the brain (microglia), the skin (Langerhans cells), kidney, heart and peritoneal cavity.This studentship will compare the transcriptomes of monocytes and macrophages from a range of mucosal tissues. These data will then be used to identify common core signatures shared in monocytes and macrophages across tissues, as well as subsets of genes restricted to cells derived from specific niches, cells with specific functions or those from different pathological diseases (homeostasis, immunosurveillance, inflammation etc.). The expression of key genes identified from these studies will then be validated in tissues using a range of cellular and bio-imaging approaches. Where data sets or materials are available the student will also determine whether the cell transcriptomes identified in this project are conserved across species.The identification of novel regulators of monocyte/macrophage function from the studies in this project may aid the development of novel therapies to improve immunosurveillance by the innate immune system or treat certain developmental or inflammatory diseases.