Final Report Summary - NORM (The genomic blueprint of macrophages: dissecting players and mechanisms through an integrative approach)
Macrophages are immune system cells present in nearly all tissues. They act both as sentinels preventing microbial invasion and as housekeeping cells participating in the removal of tissue debris and in the maintenance of tissue integrity in spite of occasional damage. Macrophages display a striking heterogeneity (commonly referred to as plasticity) that reflects the impact on their activity and functions of distinct micro-environmental signals provided by individual tissues, as well as by microbes and endogenous stress signals. Abnormal activation of a subset of macrophage gene expression programs underlies some common inflammatory diseases such as Rheumatoid Arthritis (RA) and Inflammatory Bowel Disease (IBD). Moreover, tumor-associated macrophages modulate several tumor properties and behaviors, including tumor progression and response to some therapies.The molecular roots of macrophage plasticity reside in the activation of distinct sets of genes that specify discrete functional programs required to cope with different environmental conditions, particularly those associated with an incumbent microbial danger. In turn, the activation or repression of such gene expression programs depend on a very complex set of regulatory elements scattered in our genomes and controlled by regulatory proteins (transcription factors) directly or indirectly sensitive to environmental changes. This project aimed at determining the molecular mechanisms that control macrophage function and specifically the activation of distinct gene expression programs enabling effective responses to environmental changes in physiology and disease. The studies we completed have allowed understanding the mechanisms that control the usage of the genomic regulatory information required to activate and modulate such programs. Using a combination of genomic approaches we obtained a high-resolution, mechanistic view of the essential players controlling transcriptional changes associated with macrophage differentiation and responses to stimuli. A detailed knowledge of these mechanisms will be crucial for a complete understanding of macrophage biology and for the design of pharmacological modulator of macrophage function.