Tissue-resident macrophages

Abstract

Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo.

Figure 1. Origins and renewal of tissue-resident macrophages.

Recent fate mapping studies and single cell analyses in the mouse indicate that macrophages derived early in embryogenesis from the yolk sac can contribute to adult pools of tissue ‘macrophages’, such as Langerhans cells and microglia. Other tissues may be similarly seeded or established after definitive hematopoiesis in the fetal liver or bone marrow. Proliferative local-expansion of tissue macrophages in the neonatal period, followed by low-level self-renewal during adulthood appears sufficient to maintain many tissue resident populations. During the resolution of acute inflammation, local-proliferation can be enhanced to help restore homeostatic tissue resident macrophage populations. In the context of the T_H2 environment associated with parasite infection, substantial IL-4-dependent proliferation can expand tissue resident macrophage numbers beyond that normally seen within the tissue. The exact contribution of bone marrow-derived inflammatory macrophages to these tissue resident pools is still unclear, but it appears likely to happen, although perhaps with tissue-specific variation.

Figure 2. Functions of tissue-resident macrophages.

Tissue-resident macrophages have broad roles in clearance (degradation of erythroid nuclei, senescent erythrocytes, apoptotic cells and pulmonary surfactant), development (bone degradation and angiogenesis) and the regulation of metabolism (regulation of insulin sensitivity and adaptive thermogenesis in adipose tissue). They also play a fundamental role as an immune sentinel, initiating inflammatory responses, clearing inflammatory debris and restoring homeostatic tissue environments. Neut, neutrophil; Eos, eosinophil.

Figure 3. Microanatomy of the murine spleen showing discrete localization of splenic macrophage populations.

The murine spleen has discrete red and white pulp regions separated by a marginal zone (MZ). The macrophages (MØ) of the spleen are shown in their distinct anatomical locations. The red pulp macrophages (indicated immunohistochemically by F4/80 expression: red, top) are involved in iron processing. Marginal zone and metallophilic macrophages (indicated immunohistochemically by SIGNR1 (blue, bottom) and CD169 (green) expression respectively) play roles in the capture of microbes and viruses from the circulation. Tingible body macrophages in the B cell follicles clear the apoptotic cells that result from the germinal center reaction. Immunofluorescent images were kindly provided by H. Veninga, E. Borg, G. Kraal, and J.M.M. den Haan.