Multidimensional Model of Human Macrophage Activation


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.

Keywords: innate immunity; adaptive immunity; myeloid cells; monocytes; macrophages; plasticity; cellular programming; inflammation; computational biology; systems immunology

Figure 1. Multidimensional model of macrophage activation. We propose that macrophages are influenced by three distinct sets of signals originating from ontogeny, local tissue microenvironments and stress (e.g. as part of tissue insult). During embryonic development of macrophages from erythromyeloid precursors, these cells receive differentiation signals guaranteeing cell lineage determination which – at least to a certain extend – will remain throughout the entire life of a cell, and these ontogeny‐determined cellular programmes influence macrophage activation. The overall fate and cellular programming of a macrophage under homeostatic conditions are mainly determined by tissue‐specific microenvironmental signals determining the general activation state and functionality of a macrophage. Macrophages under homeostatic conditions are never resting; they have a tissue‐specific activation state. Numerous signals can disturb tissue homeostasis. These diverse stress signals lead to further reprogramming of macrophages with different effect sizes and kinetics in macrophages derived from different tissues. Macrophage activation is further altered by previous exposure of macrophages to certain stress signals (see ‘Innate Immune Memory’).


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Aschenbrenner, Anna C, and Schultze, Joachim L() Multidimensional Model of Human Macrophage Activation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027300]