Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils

Abstract

Hematopoietic cells, including lymphoid and myeloid cells, can develop into phenotypically distinct 'subpopulations' with different functions. However, evidence indicates that some of these subpopulations can manifest substantial plasticity (that is, undergo changes in their phenotype and function). Here we focus on the occurrence of phenotypically distinct subpopulations in three lineages of myeloid cells with important roles in innate and acquired immunity: macrophages, mast cells and neutrophils. Cytokine signals, epigenetic modifications and other microenvironmental factors can substantially and, in some cases, rapidly and reversibly alter the phenotype of these cells and influence their function. This suggests that regulation of the phenotype and function of differentiated hematopoietic cells by microenvironmental factors, including those generated during immune responses, represents a common mechanism for modulating innate or adaptive immunity.

Figure 1

Macrophage populations and functional subsets. Macrophages can be subcategorized into specific populations on the basis of their anatomical location (left) and functional phenotype (right). Tissue-resident macrophages include alveolar macrophages (lungs), histiocytes (interstitial connective tissue), osteoclasts (bone), microglia (brain), intestinal macrophages, Kupffer cells (liver) and so on. Mononuclear phagocyte subpopulations in the circulation can also differentiate into tissue macrophages after entering different anatomical sites; when activated by the appropriate stimuli, these cells differentiate into various subsets with distinct phenotypic and functional characteristics.

Figure 2

Mast-cell populations and patterns of functional activation. Mast cells (MCs) in mice or humans can be subcategorized (left) into populations defined by anatomical location and/or mediator content (such as proteoglycans (heparin versus chondroitin sulfates) or proteases (tryptases, chymases or MC-CPA)). In IgE-associated immune responses to allergens or parasites (top right), the activation of mast cells via crosslinking of IgE bound to high-affinity receptors for IgE (FcεRI) on the cell surface by bi- or multivalent antigens results in rapid exocytosis of the cytoplasmic granules (degranulation) and the production of lipid mediators (such as leukotrienes and prostaglandins) and the more sustained secretion of many cytokines, chemokines and growth factors. Although many of these mediators have proinflammatory effects, others can have effects that suppress inflammation or promote tissue remodeling or repair. Signals not dependent on IgE (bottom right) can elicit different patterns of mediator release in mast-cell populations that express receptors appropriate for such ligands. Microenvironmental factors can influence the phenotype of mast cells that develop under basal conditions in different anatomic sites (left), including those phenotypic features that permit mast cells to respond to various ligands (such as the pattern of expression of receptors for those ligands) or to produce different mediators (right). TLRs are examples of the many pattern-recognition receptors expressed by various populations of mast cells. MC_T, mast cell containing mainly tryptase; MC_TC, mast cell containing both tryptase and chymase; C3a and C5a, anaphylatoxins of the complement system.

Figure 3

Features shared by ‘neutrophil MDSCs’ and neutrophils in mice with polymicrobial infection. Growth factors and cytokines generated by tumors and macrophages, as well as bacterial products, modulate the development and phenotype of neutrophils by acting both on developing neutrophils in the bone marrow and locally on neutrophils in tissues. Mast cells (not shown here) also can generate many cytokines and growth factors that can influence neutrophils, including TNF, IL-1β, GM-CSF and IL-6. Reactive oxygen species (ROS) and arginase secreted from activated neutrophils can inhibit T cell function and permit tumor growth. In this setting, such neutrophils constitute ‘neutrophil MDSCs’. LPS, lipopolysaccharide.