Control of homeostasis and inflammation by the macrophage metabolome. (360G-Wellcome-103973_Z_14_Z)

Macrophages are a heterogeneous population of immune sentinels who shape the physiology of most tissues; this fundamental role often contributes to the pathogenesis of inflammatory disorders such as rheumatoid arthritis and cancer. Recently, marked heterogeneity in tissue-resident macrophage origins has been observed, with many having prenatal rather than adult bone marrow origins. Little is currently known about how the functions of these distinct macrophage populations are controlled. However, I have observed that the phenotype of tissue-resident macrophages can be directed through tissue-specific transcription factors, which control modulators of macrophage function including metabolic regulators. I have identified extensive regulation of metabolic enzymes during an inflammatory response with a clear disparity between bone marrow-derived and tissue-resident macrophages. These enzymes have the potential to direct distinct macrophage functions through both control of the metabolome an d direct interactions with key transcription factors. I hypothesise that precise regulation of metabolic enzymes is critical for specific macrophage function. The objectives are: i) characterise the metabolomes of distinct macrophage subsets during inflammation; ii) determine functional consequences of metabolic modulation; and iii) investigate specific functions of select metabolic regulators in inflammation in-vivo. Understanding how metabolic regulation controls cell function could lead to no vel therapeutic approaches to inflammatory diseases.