The Mononuclear Phagocytic System. Generation of Diversity

Abstract

We are living through an unprecedented accumulation of data on gene expression by macrophages, reflecting their origin, distribution, and localization within all organs of the body. While the extensive heterogeneity of the cells of the mononuclear phagocyte system is evident, the functional significance of their diversity remains incomplete, nor is the mechanism of diversification understood. In this essay we review some of the implications of what we know, and draw attention to issues to be clarified in further research, taking advantage of the powerful genetic, cellular, and molecular tools now available. Our thesis is that macrophage specialization and functions go far beyond immunobiology, while remaining an essential contributor to innate as well as adaptive immunity.

Keywords: macrophage; macrophage heterogeneity; macrophage receptors; monocyte; mononuclear phagocyte; plasticity; tissue-specific function.

Figure 1

Historic figures associated with macrophages, related cells and their specialized functions.

Figure 2

Plasma membrane antigens and receptors expressed by macrophages. Macrophages are able to express a large repertoire of membrane receptors implicated in the recognition and uptake of foreign and modified self-ligands, some of which are illustrated here. These receptors incorporate a range of structural domains, illustrated schematically; they serve as useful marker antigens for immunocytochemistry and FACS analysis (e.g., F4/80, CD68, CSF-1 receptor, Mer-TK, CD64). They function as opsonic (antibody and or complement coated particles to enhance uptake via Fc and complement receptors) or non-opsonic, carbohydrate-binding lectins, and scavenger receptors. The phagocytic receptors mediate clearance of microbes (e.g., MARCO), apoptotic cells (for example CD36, SR-A, TIM4), and circulating ligands; CCR2, and CX3CR1 are examples of GPCR receptors for the monocyte/macrophage chemokines MCP-1 and fractalkine, respectively; other receptors bind growth promoting and regulatory cytokines, for example, CSF-1, and angiopoietins (Tie-2), and CD163 for clearance of injurious haptoglobin–hemoglobin complexes. Toll-like receptor-4 and CD14 react with bacterial membrane components such as lipopolysaccharide (LPS) to induce pro-inflammatory signaling; Dectin-1 recognizes fungi through beta glucan in their wall, activating a range of innate immunological responses. Siglec-1 (CD169), a receptor for sialic acid terminal glycoconjugates, mediates adhesion of host cells and microbes, whereas CD206, a receptor for clearance of Mannosyl-, fucose-, GlcNAc-terminal glycoproteins, is a prototypical marker of M2-type activation. The scavenger receptor SR-A internalizes polyanionic ligands such as modified lipoproteins, as well as selected microbes, whereas CD36 mediates adhesion and M2-induced macrophage fusion and giant cell formation. TREM-2 mutations have been implicated in neurodegeneration and osteoclast function. For further details, see BMC, with permission (28).

Figure 3

Macrophages express canonical and tissue-specific mRNA signatures. From (77) for further details, with permission. See also (78), ImmGen Consortium (79).