Educating Macrophages in vivo

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Macrophages are white blood cells which can exist in many different activation states, some of which drive tissue damage and some of which promote repair. The balance of macrophage subpopulations that exists in vivo is therefore central to controlling long term damaging responses and, as such, getting the balance right can prevent disease. Our understanding of the macrophage has grown over the last decade and it is now recognised that macrophages exist in different activation states which have different functions: the so called "M1" cell drives tissue damage whilst "M2" cells are thought to be involved in healing. Much of our understanding, and the definition of M1 and M2, however, derives from refined in vitro cell cultures and it is not known how well these ideas translate to a complex in vivo tissue environment. Thus, in vivo the macrophage may receive multiple activation signals from the tissue and may transit through different activation states. As the outcome of damage to tissues depends on the balance of M2-like cells and M1-like cells in favour of M2 it is clear that defining the driving signals in vivo is paramount. There thus remains an unmet need to enrich our understanding of the biology of the tissue macrophage in vivo. Armed with the knowledge of what important signals are, which support the M2-like cell in vivo, we can then begin developing therapies to prevent disease by enriching for this macrophage subpopulation.We have established a mouse model of gut inflammation as a robust system for defining intestinal macrophage populations and have shown that subpopulations of macrophages, firstly M1, followed by M2-like macrophages, emerge in a robust and predictable fashion. Using our model we ask whether removing specific cell signals in vivo, in the context of a complex tissue environment, prevents the emergence of the M2-like cell. In addition we address function of the tissue macrophages in the context of tissue repair, protection from damage and protection from infection.Our central hypothesis is that the balance of macrophage cell types that exist during tissue damage determines the potential for the tissue to repair. This is important for health and improved disease outcomes as it is important to prevent tissues being exposed to inflammation for prolonged periods of time.