Innate Immunity: Macrophages and Recovery from Inflammation



Innate Immunity


Macrophages and Recovery from Inflammation



Key Points



• Macrophages migrate to sites of inflammation after neutrophils. They eat and kill any surviving microbial invaders.


• Macrophages also eat dead and dying neutrophils and thus prevent damage caused by escaping neutrophil enzymes.


• Macrophages generate the powerful oxidizing agent, nitric oxide.


• Macrophages effectively remove foreign particles from the bloodstream and the respiratory tract.


• Macrophages begin the healing process in damaged tissues.


• Macrophages are essential antigen-presenting cells for the adaptive immune system.


Although neutrophils act as a first line of defense, mobilizing rapidly, converging on, and eating and killing invading microorganisms with enthusiasm, they cannot, by themselves, ensure that all invaders are killed. The body therefore employs a “backup” system employing phagocytic cells collectively known as macrophages. As phagocytic cells, macrophages differ from neutrophils in their speed of response, which is slower; in their antimicrobial abilities, which are greater; and in their ability to initiate adaptive immunity. They also act as sentinel cells and initiate tissue repair. Unlike neutrophils, which are specialized for a single task—the killing of invading organisms—macrophages have diverse functions. For this reason, many different macrophage subpopulations are recognized. It should also be pointed out that the use of two phagocytic cell systems permits cooperation between neutrophils and macrophages to enhance many aspects of innate immunity. The neutrophils tend to be of greater importance in killing extracellular pathogens, whereas the macrophages dominate in the fight against intracellular pathogens.



Macrophages


Macrophages not only detect and kill invading microorganisms, but when stimulated, they also secrete a mixture of cytokines that promote both innate and adaptive immune responses; they control inflammation; and they contribute directly to the repair of damaged tissues by removing dead, dying, and damaged cells and assist the healing process. Their name is derived from the fact that they are “large-eating” cells (Greek macro, phage).


Macrophage function and structure are highly variable, and this variation has given rise to a confusing nomenclature. Immature macrophages circulate in the bloodstream, where they are called monocytes. When monocytes emigrate into tissues, they become macrophages. Macrophages are found in connective tissue, where they are called histiocytes; those found lining the sinusoids of the liver are called Kupffer cells; those in the brain are microglia. The macrophages in the alveoli of the lungs are called alveolar macrophages, whereas those in the capillaries of the lung are called pulmonary intravascular macrophages. Large numbers are found in the sinusoids of the spleen, bone marrow, and lymph nodes. Irrespective of their name or location, they are all macrophages and all are part of the mononuclear phagocyte system (Figure 5-1).


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FIGURE 5-1 The location of the major populations of cells of the mononuclear phagocyte system.


Structure


In suspension, monocytes are round cells about 15 nm in diameter. They possess abundant cytoplasm, at the center of which is a single large nucleus that may be round, bean shaped, or indented (Figure 5-2). Their central cytoplasm contains mitochondria, large numbers of lysosomes, some rough endoplasmic reticulum, and a Golgi apparatus, indicating that they can synthesize and secrete proteins (Figures 5-3 and 5-4). In living cells, the peripheral cytoplasm is in continuous movement, forming and reforming veil-like ruffles. Many macrophages show variations in this basic structure. For example, blood monocytes have round nuclei, which elongate as the cells mature. Alveolar macrophages contain very little rough endoplasmic reticulum, but their cytoplasm is full of granules. The microglia of the central nervous system have rod-shaped nuclei and very long cytoplasmic processes (dendrites) that are lost when the cell encounters tissue damage.


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FIGURE 5-2 A typical bovine macrophage. Original magnification ×500.

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FIGURE 5-3 The major structural features of a macrophage.

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FIGURE 5-4 Transmission electron micrograph of a normal rabbit macrophage. The nature of the large inclusion is unknown. (Courtesy Dr. S. Linthicum.)


Life History


Mononuclear phagocytes develop from common myeloid stem cells in the bone marrow (Figure 5-5). During monocyte development, the myeloid stem cells give rise in sequence to monoblasts, promonocytes, and eventually to monocytes, all under the influence of cytokines called colony-stimulating factors. Monocytes enter the bloodstream and circulate for about 3 days before entering tissues and developing into macrophages. They form about 5% of the total leukocyte population in blood. It is unclear whether there are subpopulations of monocytes and whether these give rise to the specialized macrophage populations. The stage at which they leave the bloodstream may determine their function. Tissue macrophages either originate directly from monocytes or arise by division within tissues. They are relatively long-lived cells, replacing themselves at a rate of about 1% per day unless activated by inflammation or tissue damage. Macrophages may live for a long time after ingesting inert particles, such as the carbon in tattoo ink, although they may fuse together to form multinucleated giant cells in their attempts to eliminate the foreign material. Myeloid stem cells may also, when appropriately stimulated, give rise to dendritic cells. Indeed, these cells are so closely related that many investigators consider that dendritic cells are simply specialized macrophages optimized for antigen processing and presentation (Chapter 10).


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FIGURE 5-5 The origin and development of macrophages. Monocytes in blood can differentiate into many different types of macrophage. They can also differentiate into dendritic cells.


Functions


Sentinel Cells


As described in Chapter 2, macrophages express many different pattern-recognition receptors (PRRs) and readily detect and respond to invading bacteria and viruses. In addition to effective phagocytosis, they respond by producing complex cytokine mixtures. The most important of these are interleukin-1 (IL-1), IL-6, IL-12, IL-18, and tumor necrosis factor-α (TNF-α) (Figure 5-6).


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FIGURE 5-6 Some of the most important cytokines produced by macrophages and their functions.


Inflammation


Macrophages recognize tissue damage, promote the recruitment of neutrophils, and regulate the processes by which neutrophils recruit monocytes. As sentinel cells, macrophages promote neutrophil emigration from blood vessels. The release of high-mobility group band protein-1 (HMGB1) and other damage-associated molecular patterns (DAMPs) from damaged tissues stimulates resident macrophages to produce TNF-α and IL-6 as well as neutrophil chemotactic chemokines, CXCL8, CCL3, and CCL4 and reactive oxygen species.


Exosomes are small cytoplasmic vesicles, about 50 to 100 nm in diameter, that can transmit signals between cells. They are released by stimulated macrophages, dendritic cells, and B cells. These exosomes carry with them a mixture of immunostimulatory and proinflammatory molecules. They can spread through the extracellular fluid, where they interact with nearby cells. Thus exosomes from macrophages containing bacteria can express bacterial cell wall components such as glycopeptidolipids and other pathogen-associated molecular patterns (PAMPs) on their surfaces. As a result, the exosomes can bind to PRRs on nearby neutrophils and macrophages, leading to MyD88-dependent release of TNF-α, CCL5, and iNOS and promoting more inflammation.



Phagocytosis


When microbial invasion occurs and inflammation develops, blood monocytes respond by binding to vascular endothelial cells in a manner similar to neutrophils. Thus adherence and rolling are triggered by selectin binding, and the cells are brought to a gradual halt by integrins binding to ligands on vascular endothelial cells. The monocytes bind to endothelial cell intracellular adhesion molecule 1 (ICAM-1), using β2-integrins and then emigrate into the tissues. Within the tissues these cells are called macrophages. Several hours after neutrophils have entered an inflammatory site, the macrophages arrive. These macrophages are attracted not only by bacterial products and complement components such as C5a but also by DAMPs from damaged cells and tissues. Once neutrophils have emigrated into tissues, they also attract macrophages. Thus neutrophil granules contain macrophage chemoattractants such as azurocidin, defensins, and cathelicidins. Activated neutrophils and endothelial cells produce monocyte chemoattractant protein-1 (CCL2) under the influence of IL-6. Neutrophils are the martyrs of the immune system: they reach and attack foreign material first, and in dying they attract macrophages to the site of invasion. Phagocytosis by macrophages is similar to the process in neutrophils. Macrophages destroy bacteria by both oxidative and nonoxidative mechanisms. In contrast to neutrophils, however, macrophages can undertake sustained, repeated phagocytic activity. In addition, macrophages release collagenases and elastases that destroy nearby connective tissue. They release plasminogen activator that generates plasmin, another potent protease. Thus macrophages can “soften up” the local connective tissue matrix and permit more effective penetration of the damaged tissue. Macrophages phagocytose both apoptotic neutrophils and their exosomes. The contents of neutrophil granules are not always destroyed but may be carried to macrophage endosomes where they can continue to inhibit the growth of bacteria. Thus neutrophils can enhance the effectiveness of macrophages in host defense.



Generation of Nitric Oxide


In some mammals, especially rodents, cattle, sheep, and horses (but not in humans, pigs, goats, or rabbits), microbial PAMPs trigger macrophages to synthesize inducible nitric oxide synthase (iNOS or NOS2). This enzyme acts on L-arginine using NADPH and oxygen to produce large amounts of nitric oxide (nitrogen monoxide, NO) and citrulline (Figure 5-7). Nitric oxide alone is not highly toxic, but it can react with superoxide anion to produce potent oxidants such as peroxynitrite and nitrogen dioxide radical.


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FIGURE 5-7 The two pathways of arginine metabolism in macrophages. The production of nitric oxide through the use of nitric oxide synthase 2 is a major antimicrobial pathway and the key feature of M1 macrophages. The use of arginase to produce ornithine, however, reduces the antimicrobial activities of M2 cells.
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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Innate Immunity: Macrophages and Recovery from Inflammation

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