Multidimensional Model of Human Macrophage Activation

Abstract

Macrophages are extremely versatile cells, distributed throughout all tissues, involved in numerous functions, and equipped with many sensing receptors and effector molecules. They are critical during embryogenesis, key players in organ homeostasis and orchestrators during any kind of tissue insult, whether induced by the outside world or inside stress signals. Moreover, macrophages are involved in all major common diseases our societies are suffering from. Therefore, it is of utmost importance to understand how macrophage activation is regulated and orchestrated. For a long time, macrophage activation was divided into either proinflammatory or anti‐inflammatory activation. In fact, previous experimental approaches favoured such dichotomous models of macrophage activation. However, with the advent of the generation of high‐throughput data, this view on macrophage activation has dramatically changed by realising the enormous plasticity of these cells. To describe such plasticity, and based on computational modelling of transcriptome data, we have introduced the multidimensional model of macrophage activation. This model showcases the capability of macrophages of integrating signals they derive from their microenvironment to signal input‐specific functional programmes. Collectively, this new model combines findings derived from macrophage ontogeny, tissue macrophage biology and inflammation research in diseases. Key Concepts Macrophages are one of the most versatile cell populations within multicellular organisms. Macrophages exhibit enormous plasticity. Macrophages integrate signals from their microenvironment, which results in signal input‐specific functional outcomes. The multidimensional model of macrophage activation describes the input‐specific cellular programming of macrophages in response to stimulation. This model opens new avenues to more specific targeting of macrophages in disease settings. The paradigm shift from a bipolar to a multidimensional model of macrophage activation required large data and computational modelling, illustrating the power of systems immunology to understand immune cell phenotypes and function.