Neutrophils and macrophages that are recruited into sites of infections ingest microbes into vesicles by the process of phagocytosis and destroy these microbes (Fig. 1). Phagocytosis is an active, energy-dependent process of engulfment of large particles (greater than 0.5 μm in diameter) into vesicles. Phagocytic vesicles fuse with lysosomes and the ingested particles are destroyed by lysosomal enzymes. In this way, the mechanisms of killing, which could potentially injure the phagocyte, are isolated from the rest of the cell.

Fig1. Phagocytosis and intracellular destruction of microbes. Microbes may be ingested by different membrane receptors of phagocytes; some directly bind microbes and others bind opsonized microbes. The microbes are internalized into phagosomes, which fuse with lysosomes to form phagolysosomes, where the microbes are killed by reactive oxygen and nitrogen species and proteolytic enzymes. IgG, Immunoglobulin G; iNOS, inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species.

Neutrophils and macrophages express receptors that specifically recognize microbes; binding of microbes to these receptors is the first step in phagocytosis. Some of these receptors are pat tern recognition receptors, including C-type lectins and scavenger receptors, which we discussed earlier. Pattern recognition receptors can contribute to phagocytosis only of organisms that express particular molecular patterns, such as mannose for the mannose receptor. Phagocytes also have high-affinity receptors for certain opsonins, including antibody molecules, complement proteins, and plasma lectins; these receptors are critical for phagocytosis of many different microbes that are coated with the opsonins. Coating microbes with antibodies is one of the most efficient systems for opsonization. Phagocytes express a high-affinity Fc receptor called FcγRI, specific for one type of antibody called IgG. Thus, if an individual responds to an infection by making IgG antibodies against microbial antigens, the IgG molecules bind to these antigens, the Fc ends of the bound antibodies can interact with FcγRI on phagocytes, and the end result is efficient phagocytosis of the microbes. Antibody-dependent phagocytosis illustrates a link between innate and adaptive immunity—antibodies are a product of the adaptive immune system (B lymphocytes) that engages innate immune system effector cells (phagocytes) to perform their protective functions.

Once a microbe or particle binds to receptors on a phagocyte, the plasma membrane in the region of the receptors begins to invaginate and extends a cup-shaped projection around the microbe. When the protruding membrane cup extends beyond the diameter of the particle, the top of the cup closes over and pinches off the interior of the cup to form an inside-out intracellular vesicle (see Fig. 1). This vesicle, called a phagosome, contains the ingested foreign particle. It breaks away from the plasma membrane and fuses with a lysosome, where the next step in the process, the destruction of the ingested particle, occurs.

Activated neutrophils and macrophages kill phagocytosed microbes by the action of microbicidal molecules in phagolysosomes (see Fig. 1). Signals from various receptors, including pattern recognition receptors (such as TLRs), opsonin receptors (such as Fc and C3b receptors), receptors for cytokines (mainly IFN-γ), and CD40, function cooperatively to activate phagocytes to kill ingested microbes. The fusion of phagocytic vacuoles (phagosomes) with lysosomes results in the formation of phagolysosomes, where most of the microbicidal mechanisms are concentrated. Three classes of microbicidal molecules are known to be the most important.

• Reactive oxygen species (ROS). Activated neutrophils and macrophages convert molecular oxygen into ROS, which are highly reactive free radicals that destroy microbes (and other cells). The primary free radical–generating system is the phagocyte (NADPH) oxidase system. Phagocyte oxidase is a multisubunit enzyme that is assembled in activated phagocytes, mainly in the phagolysosomal membrane. Phagocyte oxidase is activated by many stimuli, including IFN-γ and signals from TLRs. The function of this enzyme is to chemically reduce molecular oxygen into ROS, such as superoxide radicals, with the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) acting as a cofactor. Superoxide is enzymatically dismutated into hydrogen peroxide, which is used by the enzyme myeloperoxidase to convert normally unreactive halide ions into reactive hypohalous acids that are toxic for bacteria. The process by which ROS are produced is called the respiratory burst because it requires oxygen consumption (cellular respiration). A dis ease called chronic granulomatous disease is caused by an inherited deficiency of one of the components of phagocyte oxidase; this deficiency compromises the capacity of phagocytes to kill certain species of bacteria.

 • Nitric oxide (NO). Macrophages produce reactive nitrogen species, mainly NO, by the action of an enzyme called inducible nitric oxide synthase (iNOS). iNOS is a cytosolic enzyme that is absent in resting macrophages but is induced in response to microbial products that activate TLRs, especially in combination with IFN-γ. iNOS catalyzes the conversion of arginine to citrulline and freely diffusible NO gas is released. Within phagolysosomes, NO may combine with hydrogen peroxide or superoxide, generated by phagocyte oxidase, to produce highly reactive peroxynitrite radicals that can kill microbes. The cooperative and redundant function of ROS and NO is demonstrated by the finding that knockout mice lacking both iNOS and phagocyte oxidase are more susceptible to bacterial infections than single phagocyte oxidase or iNOS knockout animals.

• Proteolytic enzymes. Activated neutrophils and macrophages produce several proteolytic enzymes in the phagolysosomes that function to destroy microbes. One of the important enzymes in neutrophils is elastase, a broad-spectrum serine protease known to be required for killing many types of bacteria. Another important enzyme is cathepsin G. Mouse gene knockout studies have confirmed the essential requirement for these enzymes in phagocyte killing of bacteria.

Microbes within macrophages may also be killed when the macrophages undergo inflammasome-mediated pyroptosis, as described earlier.

Neutrophils also kill microbes by extruding their DNA and granule contents, which form extracellular threads on which bacteria and fungi are trapped and killed. The extruded chromatin contents, which are called neutrophil extracellular traps (NETs), are composed of strands of DNA and histones to which high concentrations of antimicrobial granule contents are bound, including lysozyme, elastase, and defensins. NET formation requires citrullination of histones by the enzyme peptidylarginine deiminase (PAD4), as well as neutrophil serine protease elastase, myeloperoxidase, and phagocyte oxidase. The extrusion of nuclear contents during NET formation usually leads to neutrophil cell death, referred to as NETosis. The importance of NETs in innate protection against infections remains unclear, but growing evidence indicates that excessive NET formation contributes to autoimmune and other inflammatory diseases.

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مواضيع ذات صلة

Immuno microscopy

V(D)J Recombination

Role of Macrophages in Tissue Repair

Sequence of Events in Inflammation: Vascular Changes and Leukocyte Migration Into Tissues

Double Antibody Sandwich ELISA (DAS ELISA)

Enzyme Immunosorbent Assays

Antibody Structure and Function

Apoptosis in the Immune System

The Major Proinflammatory Cytokines of Innate Immunity: Interleukin-6

The Major Proinflammatory Cytokines of Innate Immunity: Interleukin-1

The Major Proinflammatory Cytokines of Innate Immunity: Tumor Necrosis Factor

The Immune Receptor Family