Macrophages: gatekeepers of tissue integrity

Abstract

Macrophages form a heterogeneous group of hematopoietic cells that reside in tissues, where they are required to maintain organ integrity. Tissue macrophages contribute to tissue formation, metabolism, homeostasis, and repair. They have a unique ability to sense and respond to tissue damage. They serve as the first line of defense during infection and help promote immune tolerance in the steady state. Although most tissue macrophages share a high phagocytic and degradative potential, they are heterogeneous in origin, as well as in homeostatic function and response to insults. Here, we will discuss recent developments in our understanding of the origin of tissue macrophages and their functional specialization in tissues.

Figure 1

Macrophage heterogeneity. Macrophages are a heterogeneous population of tissue-resident hematopoietic cells. This figure illustrates key cell surface markers of mouse macrophage and monocyte populations. Macrophages can be identified by a combination of cell surface markers, including the hematopoietic lineage marker CD45, the integrin CD11b, and the GPCR F4/80, among other markers. However, macrophages in different organs have different compositions and expression levels of these cell surface proteins, reflecting their inherent diversity. CD169, sialoadhesin, is an important marker in certain macrophage populations such as the bone marrow, spleen, and lung. CX3CR1 helps to identify macrophages in the intestine and differentiate the blood monocyte subsets.

Figure 2

Regulation of macrophage development and homeostasis in mice. This figure summarizes the current model of the pathways to the development of nonlymphoid tissue-resident macrophages. Most tissue-resident macrophages in the steady state arise from embryonic precursors that are recruited to tissues before birth with the exception of intestinal and spleen marginal zone macrophages that derive from circulating monocytes. Embryonic precursor-derived macrophages receive trophic signals that depend upon their particular locations. Microglia and Langerhans cells require interleukin (IL)-34, alveolar macrophages depend on CSF2, and splenic red pulp macrophages use CSF1 for tissue maintenance. The successive steps that give rise to circulating monocytes in the adult bone marrow have been characterized. Adult bone marrow hematopoietic stem cells (HSC) give rise to the common myeloid precursors (CMP), which subsequently give rise to the MDP. MDP produce both the cMoP and the CDP. CDP differentiate in response to Flt3 ligand into pre-dendritic cells (pre-DC), which migrate through the blood to peripheral tissues and differentiate locally into dendritic cells. cMoP give rise to circulating monocytes that survey the blood for the presence of foreign pathogens and damaged cells. Ly6C^hi monocytes differentiate into Ly6C^lo cells, which have been shown to control vessel integrity and to give rise to splenic marginal zone (MZ) macrophages. Ly6C^hi monocytes also give rise to intestinal macrophages in the steady state and differentiate into inflammatory macrophages in most injured tissues.