Origins and diversity of macrophages in health and disease

Abstract

Macrophages are the first immune cells in the developing embryo and have a central role in organ development, homeostasis, immunity and repair. Over the last century, our understanding of these cells has evolved from being thought of as simple phagocytic cells to master regulators involved in governing a myriad of cellular processes. A better appreciation of macrophage biology has been matched with a clearer understanding of their diverse origins and the flexibility of their metabolic and transcriptional machinery. The understanding of the classical mononuclear phagocyte system in its original form has now been expanded to include the embryonic origin of tissue-resident macrophages. A better knowledge of the intrinsic similarities and differences between macrophages of embryonic or monocyte origin has highlighted the importance of ontogeny in macrophage dysfunction in disease. In this review, we provide an update on origin and classification of tissue macrophages, the mechanisms of macrophage specialisation and their role in health and disease. The importance of the macrophage niche in providing trophic factors and a specialised environment for macrophage differentiation and specialisation is also discussed.

Keywords: innate immunity; macrophage diversity; macrophage functions; macrophage niche; macrophage origins.

Figure 1

Origin of macrophages. Myeloid cells including macrophages arise from three successive haematopoietic waves, referred to as primitive, pro‐definitive and definitive. The primitive programme starts at embryonic days 6.5 (E6.5)‐E8.5 in the blood islands of the extraembryonic yolk sac (YS) and gives rise to nucleated erythrocytes, megakaryocytes and Mac‐CFCs. The pro‐definitive wave starts at E8.5 and E10.5 in the yolk sac, allantois and embryo proper and gives rise to erythroid and myeloid progenitors (EMPs). Primitive and pro‐definitive phases contribute to microglia, Langerhans and Kupffer cells. The third wave of definitive haematopoiesis starts at E10.5 from the aorta–gonad–mesonephros region (AGM) region and gives rise to LT‐HSC. They migrate to the foetal liver and definitive haematopoiesis shifts to BM around E17.5. Definitive haematopoietic stem cells give rise to Kupffer cells and alveolar macrophage tissue residing in cardiac system, skeletal muscle, dermis and gut.

Figure 2

The heterogenous functions of tissue macrophages. All tissue macrophages go through a process of lineage determination via expression of limited set of transcription factors to acquire functions and cell surface markers common to all macrophages (phagocytosis, F4/80, MertK). The tissue microenvironment customises the macrophage to take over organ‐specific functions by inducing expression of unique set of transcription factors. Multiple signals specific to a tissue in a sequential combination are required to prime the macrophage and prepare the epigenetic landscape for macrophages to take up a tissue‐specific identity.