Fate-Mapping Macrophages: From Ontogeny to Functions.

Macrophages are vital to the physiological function of most tissues, but also contribute to disease through a multitude of pathological roles. They are thus highly plastic and heterogeneous. It is now well recognized that macrophages develop from several distinct progenitors from embryogenesis onwards and extending throughout life. Tissue-resident macrophages largely originate from embryonic sources and in many cases self-maintain independently without monocyte input. However, in certain tissues, monocyte-derived macrophages replace these over time or as a result of tissue injury and inflammation. This additional layer of heterogeneity has introduced many questions regarding the influence of origin on fate and function of macrophages in health and disease. To comprehensively address these questions, appropriate methods of tracing macrophage ontogeny are required. This chapter explores why ontogeny is of vital importance in macrophage biology and how to delineate macrophage populations by origin through genetic fate mapping. First, we summarize the current view of macrophage ontogeny and briefly discuss how origin may influence macrophage function in homeostasis and pathology. We go on to make the case for genetic fate mapping as the gold standard and briefly review different fate-mapping models. We then put forward our recommendations for fate-mapping strategies best suited to answer specific research questions and finally discuss the strengths and limitations of currently available models.

Developmental programming of macrophages by early life adversity.

Macrophages are central elements of all organs, where they have a multitude of physiological and pathological functions. The first macrophages are produced during fetal development, and most adult organs retain populations of fetal-derived macrophages that self-maintain without major input of hematopoietic stem cell-derived monocytes. Their developmental origins make macrophages highly susceptible to environmental perturbations experienced in early life, in particular the fetal period. It is now well recognized that such adverse developmental conditions contribute to a wide range of diseases later in life. This chapter explores the notion that macrophages are key targets of environmental adversities during development, and mediators of their long-term impact on health and disease. We first briefly summarize our current understanding of macrophage ontogeny and their biology in tissues and consider potential mechanisms by which environmental stressors may mediate fetal programming. We then review evidence for programming of macrophages by adversities ranging from maternal immune activation and diet to environmental pollutants and toxins, which have disease relevance for different organ systems. Throughout this chapter, we contemplate appropriate experimental strategies to study macrophage programming. We conclude by discussing how our current knowledge of macrophage programming could be conceptualized, and finally highlight open questions in the field and approaches to address them.