Transcriptional programming of human macrophages: on the way to systems immunology.

Many of the major common diseases such as atherosclerosis, diabetes, obesity, numerous autoimmune diseases, as well as neurodegenerative diseases such as Alzheimer's disease and many cancer types are characterised by a chronic inflammatory component termed sterile inflammation. Myeloid cells, particularly macrophages, are an important cellular component of chronic inflammation in these diseases. For almost all of these disease conditions, previous reports suggested that macrophages can exert either so-called pro-inflammatory or anti-inflammatory functions, thereby either fighting or feeding the disease. This apparent dichotomy of reactions of macrophages led to a dichotomous definition of macrophage activation classified as macrophage polarisation. However, analysis of large transcriptomics data derived from human and murine macrophages show that macrophage functions are shaped in a very tissue- and signal-input specific manner, allowing these cells to develop extremely specific functional programmes. Integrating global views on macrophage activation on the transcriptome, the epigenome, the proteome or the metabolome will finally lead to a data-driven approach to understand macrophage biology in context of major diseases. We are indeed on the way to a systems immunology approach that integrates -omics data with mathematical and bioinformatical modelling as the pre-requisite to generate data-driven hypotheses. This approach opens completely new avenues for the development of tailored diagnostics and therapies targeting macrophages in sterile inflammations of the major common diseases. I will also discuss some of the next developments that will be necessary to reach these important goals.