Classic and new mediators for in vitro modelling of human macrophages

Macrophages are key immune cells in the activation and regulation of immune responses. These cells are present in all tissues under homeostatic conditions and in many disease settings. Macrophages can exhibit a wide range of phenotypes depending on local and systemic cues that drive the differentiation and activation process. Macrophage heterogeneity is also defined by their ontogeny. Tissue macrophages can either derive from circulating blood monocytes or are seeded as tissue-resident macrophages during embryonic development. In humans, the study of in vivo-generated macrophages is often difficult with laborious and cell-changing isolation procedures. Therefore, translatable, reproducible, and robust in vitro models for human macrophages in health and disease are necessary. Most of the methods for studying monocyte-derived macrophages are based on the use of limited factors to differentiate the monocytes into macrophages. Current knowledge shows that the in vivo situation is more complex, and a wide range of molecules in the tissue microenvironment promote and impact on monocyte to macrophage differentiation as well as activation. In this review, macrophage heterogeneity is discussed and the human in vitro models that can be applied for research, especially for monocyte-derived macrophages. We also focus on new molecules (IL-34, platelet factor 4, etc.) used to generate macrophages expressing different phenotypes.