Phagocytes, including neutrophils and macrophages, are cells whose primary function is to ingest and destroy microbes and remove damaged tissues. The functional responses of phagocytes in host defense consist of sequential steps: recruitment of the cells to the sites of infection, recognition of and activation by microbes, ingestion of the microbes by the process of phagocytosis, and destruction of ingested microbes. In addition, through direct contact and by secreting cytokines, phagocytes communicate with other cells in ways that promote or regulate immune responses.

Neutrophils and monocytes are produced in the bone marrow, circulate in the blood, and are recruited to sites of inflammation. Monocytes differentiate into macrophages after entering tissues. Although both are actively phagocytic, neutrophils and macrophages differ in significant ways (Table 1). The neutrophil response is more rapid and the life span of these cells after they enter tissues is short, whereas macrophages can live for long periods so that the macrophage response may last for a prolonged time. Neutrophils mainly use cytoskeletal rearrangements and enzyme activation to mount rapid, transient responses, whereas macrophage responses rely more on induced gene transcription and protein expression. In addition, as we discuss later, there are populations of macrophages that normally reside in healthy tissues, but neutrophils do not. The functions of phagocytes are important in innate immunity and also in the effector phase of some adaptive immune responses. As a prelude to more detailed discussions of the role of phagocytes in immune responses in later chapters, here we will describe the development and morphologic features of neutrophils and macrophages and briefly introduce their functional responses.

Table1. Distinguishing Properties of Neutrophils and Macrophages

Neutrophils

Neutrophils are the most abundant population of circulating white blood cells and the principal cell type in acute inflammatory reactions. Neutrophils circulate as spherical cells approximately 12 to 15 μm in diameter with numerous membranous projections. The nucleus is segmented into three to five connected lobules (Fig.1A). Because of their nuclear morphology, neutrophils are also called polymorphonuclear leukocytes (PMNs) to contrast them with mononuclear cells (macrophages and lymphocytes), whose nuclei are not multilobed. Neutrophil cytoplasm contains two types of membrane-bound granules. The majority of these, called specific granules, are filled with enzymes, such as lysozyme, collagenase, and elastase. Specific granules do not stain strongly with either basic or acidic dyes (hematoxylin and eosin, respectively), which distinguishes neutrophils from two other types of circulating leukocytes with cytoplasmic granules, called basophils and eosinophils. The remainder of the granules of neutrophils, called azurophilic granules because they are stained by dye called azure A, contain enzymes (e.g., myeloperoxidase) and microbicidal substances, including defensins and cathelicidins. Neutrophils arise from precursors in the bone mar row that also give rise to circulating monocytes. Production of neutrophils is stimulated by granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). An adult human produces more than 1 × 10¹¹ neutrophils per day, each of which circulates in the blood from a few hours to up to 5 days before dying. Neutrophils may migrate to sites of infection rapidly after the entry of microbes. After entering tissues, neutrophils function for only a few days before most of them then die.

Fig1. Morphology of neutrophils, mast cells, basophils, and eosinophils. (A) The light micrograph of a Wright-Giemsa–stained blood neutrophil shows the multilobed nucleus, because of which these cells are also called polymorphonuclear leukocytes, and the faint cytoplasmic granules. (B) The light micrograph of a Wright-Giemsa–stained section of skin shows a mast cell (arrow) adjacent to a small blood vessel, identifiable by the red blood cell in the lumen. The cytoplasmic granules in the mast cell, which are stained purple, are filled with histamine and other mediators that act on adjacent blood vessels to promote increased blood flow and delivery of plasma proteins and leukocytes into the tissue. (C) The light micrograph of a Wright-Giemsa–stained blood basophil shows the characteristic blue-staining cytoplasmic granules. (D) The light micrograph of a Wright-Giemsa–stained blood eosinophil shows the characteristic segmented nucleus and red staining of the cytoplasmic granules. B, Courtesy Dr. George Murphy, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts. C, Courtesy Dr. Jonathan Hecht, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.

The major function of neutrophils is to phagocytose microbes, especially opsonized microbes, and products of necrotic cells and destroy these in phagolysosomes. In addition, neutrophils may secrete granule contents and can extrude their nuclear contents, forming neutrophil extracellular traps (NETs), which serve to immobilize and kill extra cellular microbes but also may damage healthy tissues.

Mononuclear Phagocytes

The mononuclear phagocyte system includes circulating bone marrow–derived cells called monocytes, many of which become macrophages when they migrate into tissues, and tis sue-resident macrophages, which are initially derived from a yolk sac or hematopoietic precursors during fetal life.

Development of Monocytes and Macrophages. After birth, cells of the monocyte-macrophage lineage arise from commit ted precursor cells in the bone marrow, driven by a cytokine called a monocyte (or macrophage) colony-stimulating factor (M-CSF). These precursors mature into monocytes, which enter and circulate in the blood (Fig. 2A), where they have a short life span of approximately 1 to 7 days. Blood monocytes are efficiently recruited into tissue sites of infection or injury, where they differentiate (mature) into macrophages and therefore most macrophages at sites of inflammation are derived from monocytes.

Fig2. Maturation of mononuclear phagocytes. (A) Pathways of macrophage development. During inflammatory reactions, precursors in the bone marrow give rise to circulating monocytes, which enter peripheral tissues and mature to form short-lived macrophages, which are activated locally. Many tissue-resident macrophages develop in fetal life from primitive hematopoietic precursors in the yolk sac and hematopoietic precursors in the fetal liver and bone marrow. Blood monocytes may contribute to the tissue-resident pool of macrophages in postnatal life to varying degrees between different tissues.

Fig. 2, cont’d (B) The relative contributions of precursors from the yolk sac, fetal liver, and postnatal bone marrow to macrophages resident in different tissues in the steady state, as determined by cell fate mapping studies in mice. B, Courtesy Florent Ginhoux and Svetoslav Chakarov. Modified from Ginhoux F, Guillams M. Tissue-resident macrophage ontogeny and homeostasis. Immunity. 2016;44:439–449.

Most tissue-resident macrophages are long-lived and are derived not from the bone marrow but from yolk sac or fetal liver precursors during fetal development. These cells have self-renewal capacity, so they can maintain stable numbers. Some examples of tissue-resident macrophages are Kupffer cells lining the sinusoids in the liver, alveolar macrophages in the lung, and microglial cells in the brain (Fig. 2B). In the steady state, blood monocytes are recruited at a low rate into healthy tissues, where they may differentiate into tissue resident macrophages. This pathway of monocyte differentiation into tissue macrophages supplements the self-renewal of the fetally derived cells, and accounts for varying fractions of resident macrophages in different tissues.

Subsets of Monocytes. Monocytes are 10 to 15 μm in diameter, and they have bean-shaped nuclei and a finely granular cytoplasm containing lysosomes, phagocytic vacuoles, and cytoskeletal filaments (Fig. 3). All human monocytes express major histocompatibility complex (MHC) class II molecules, CD11b, and CD86, and all mouse monocytes express CD115, CD11b, and CD64. However, monocytes are heterogeneous and consist of different subsets distinguishable by cell surface markers and functions, but not by morphology. In both humans and mice, the most numerous monocytes, called classical or inflammatory monocytes (comprising 90%–95% of blood monocytes in humans), produce inflammatory mediators, are phagocytic, and are rapidly recruited to sites of infection or tissue injury. A second type of circulating monocyte, called nonclassical monocytes (5%–10% of blood monocytes), are recruited into tissues after infection or injury and engage in phagocytosis of microbes and may contribute to repair of damaged tissues. Some non-classical monocytes are known to crawl along endothelial sur faces (described as patrolling), where they scavenge luminal microparticles and may play a role in eliminating circulating microbes and in repairing endothelial barrier defects.

Fig3. Morphology of mononuclear phagocytes. (A) Light micrograph of a monocyte in a peripheral blood smear. (B) Electron micrograph of a peripheral blood monocyte. (C) Electron micrograph of an activated tissue macrophage showing numerous phagocytic vacuoles and cytoplasmic organelles. Courtesy Dr. Noel Weidner, Department of Pathology, University of California, San Diego.

Functions of Macrophages. Macrophages play crucial roles in innate and adaptive immune responses to infections and in the repair of damaged tissues (Fig. 4).

• A major function of monocyte-derived macrophages in host defense is to ingest microbes by the process of phagocytosis and then to kill the ingested microbes. The mechanisms of phagocytosis and killing, include the formation of cytoplasmic membrane-bound organelles that contain the microbes, the fusion of these organelles with lysosomes, the enzymatic generation of reactive oxygen and nitro gen species in the lysosome that are toxic to microbes, and the digestion of microbial proteins by proteolytic enzymes.

• Tissue-resident macrophages function as sentinel cells that sense the presence of microbes and respond by secreting cytokines that initiate and then amplify the protective response against the microbes. Some of these cytokines act on endothelial cells lining blood vessels to enhance the recruitment of monocytes and other leukocytes from the blood into sites of infections. Other cytokines made by activated macrophages act on leukocytes and stimulate their migration to tissue sites of infection or damage.

• Macrophages that have engulfed microbes can be induced by microbial molecules to undergo an inflammatory form of death called pyroptosis, which usually results from the activation of a cytoplasmic enzyme complex called the inflammasome. Pyroptosis leads to the release of cytokines that enhance the host’s inflammatory response to the infection.

• In addition to ingesting microbes, macrophages ingest necrotic host cells, including cells that die in tissues because of the effects of toxins, trauma, or interrupted blood supply, and neutrophils that die after accumulating at sites of infection. This is part of the cleaning-up process after infection or sterile tissue injury. Macrophages also can specifically recognize and engulf cells that die by apoptosis before the dead cells can release their contents and induce inflammatory responses. This clearance of apoptotic cells by macrophages is called efferocytosis. Throughout the body and throughout the life of an individual, unwanted cells die by apoptosis as part of many physiologic processes, such as development and renewal of healthy tissues and maintenance of cell numbers (tissue homeostasis), and the dead cells are eliminated by macrophages.

 • Macrophages serve as antigen-presenting cells (APCs) that display fragments of protein antigens to T lymphocytes and activate T cells recruited to sites of injury or infection. This function is important in the effector phase of T cell–mediated immune responses.

 • Subcapsular sinus macrophages and marginal zone macrophages in lymphoid tissues can bind antigens and then hand them over to B cells and follicular dendritic cells. This is important for intitiation of humoral immune responses.

• Macrophages promote the repair of damaged tissues by stimulating new blood vessel growth (angiogenesis) and the synthesis of collagen-rich extracellular matrix (fibrosis). These functions are mediated by cytokines secreted by the macro phages that act on various tissue cells.

 • Tissue-resident macrophages also perform specialized organ specific functions. For example, Kupffer cells in the liver support systemic metabolism, alveolar macrophages in the lung regulate surfactant levels by phagocytosis and catabolism, gut lamina propria macrophages support intestinal stem cell differentiation, and microglia in the brain are involved in synaptic pruning.

Fig4. Functions of macrophages. Macrophages are activated by microbial products such as lipopolysaccharides and by natural killer cell–derived interferon-γ (IFN-γ). The process of macrophage activation leads to the activation of transcription factors, the transcription of various genes, and the synthesis of proteins that mediate the functions of these cells. In adaptive cell-mediated immunity, macrophages are activated by stimuli from T lymphocytes (CD40 ligand and IFN-γ) and respond in essentially the same way. Macrophages also may be activated by other signals to promote tissue repair and fibrosis (not shown). IgG, Immunoglobulin G; IL, interleukin; iNOS, inducible nitric oxide synthase; TIM4, T-cell immunoglobulin 4.

Monocyte-derived macrophages may respond to microbes nearly as rapidly as neutrophils do, but macrophages survive much longer at sites of inflammation. Unlike neutrophils, macrophages can undergo cell division at an inflammatory site. Therefore, macrophages are the dominant effector cells in the later stages of innate immune responses, several days after an infection begins.

Macrophage Receptors and Activation. Macrophages are activated to perform their functions by recognizing many different kinds of microbial molecules, as well as host molecules produced in response to infections and injury. These various activating molecules bind to specific signaling receptors located on the surface of the macrophage (see Fig. 4). An example are Toll-like receptors (TLRs), which serve important roles in innate immunity.

Macrophages are also activated when other plasma membrane receptors bind opsonins on the surface of microbes. Opsonins are substances that coat microbial cells or other particles and thereby target them for phagocytosis. Examples of opsonin receptors are complement receptors, which bind fragments of complement proteins attached to microbial surfaces, and immunoglobulin G (IgG) Fc receptors, which bind to one end of IgG antibody molecules that already have microbes bound at the other end. Macrophage phagocytosis of healthy host cells is prevented in part by an inhibitory receptor on the macrophage called SIRPα, which recognizes CD47, a membrane protein on healthy cells that functions as a “don’t eat me” signal. When CD47 binds to SIRPα, inhibitory signals are generated in the macrophage that prevent phagocytosis. In adaptive immunity, macrophage antimicrobial functions are activated by some T-lymphocyte cytokines and membrane proteins that bind to signaling receptors on the macrophage membrane.

Subsets of Macrophages. Macrophages can acquire dis tinct functional capabilities in response to different types of activating stimuli. The clearest example of this is the activation of macrophages by different cytokines made by subsets of T cells. Some of these cytokines activate macrophages to become efficient at killing microbes, called classical activation, and these cells are often called M1 macrophages. Other cytokines activate macrophages to promote tissue remodeling and repair, called alternative activation, and these cells are called M2 macrophages. Analyses of phenotypes and transcriptional profiles indicate that multiple macrophage subsets exist that do not neatly fall into M1 or M2 categories. The relationship between blood monocyte subsets, discussed earlier, and M1-like and M2-like macrophage sub sets is not well understood. Macrophages may also assume different morphologic forms after activation by external stimuli, such as microbes. Some develop abundant cytoplasm and are called epithelioid cells because of their resemblance to epithelial cells of the skin. Activated macrophages can fuse to form multinucleated giant cells, which occurs frequently in certain types of microbial infections, such as with mycobacteria, and in response to indigestible foreign bodies.

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Development of Lymphocytes

Dendritic Cells

Mast Cells, Basophils, and Eosinophils

Major Features of Cell-Mediated Immunity

Major Features of Humoral Immunity

Initiation and Development of Adaptive Immune Responses

Chemokines and Chemokine Receptors

Overview of Humoral and Cell-Mediated Immunity

Fundamental Properties of Adaptive Immune Responses

Colitis, Autoimmunity, and Primary Immunodeficiencies

Hemophagocytic lymphohistiocytosis

Allergic Rhinitis