Mechanisms of Phagocytic Recognition, Engulfment, and Killing

The term phagocytosis literally means “eating cell process.” But phagocytosis is more than just the physical act of engulfment, because phagocytes also actively attack and dismantle foreign cells with a wide array of antimicrobial substances. Phagocytosis can occur as an isolated event performed by a lone phagocytic cell responding to a minor irritant in its area or as part of the orchestrated events of inflammation. The events in phagocytosis include chemotaxis, ingestion, phagolysosome formation, destruction, and elimination (figure 2).

Fig. 1. The developmental stages of monocytes and macrophages. The cells progress through maturational stagesin the bone marrow and peripheral blood. Once in the tissues, amacrophage can remain nomadic or take up residence in a specific organ.

Chemotaxis, Binding, and Ingestion Phagocytes migrate into a region of inflammation with a deliberate sense of direction, attracted by a gradient of stimulant products from the pathogen and host tissue at the site of injury.

Once a phagocyte encounters the pathogen, it uses its toll-like receptors (TLRs) to make contact with the pathogen (figure 2). TLRs are receptors that recognize and bind the PAMP receptors of various microbes. There are about 10 different TLRs in the membranes of phagocytes. The exposed end of a receptor hooks on to a PAMP and immediately dimerizes or joins with a second TLR to encase the molecule (figure 3). This relays a signal into the nucleus that stimulates the intracellular phagocytic processes and the release of chemical mediators.

On the scene of an inflammatory reaction, phagocytes often trap cells or debris against the fibrous network of connective tissue or the wall of blood and lymphatic vessels. Once the phagocyte has “caught” its prey, it extends pseudopods that enclose the cells or particles in a pocket and internalize them in a vacuole called a phagosome.

Fig. 2. The sequential events in phagocytosis. (1) Phagocyte isattracted to bacteria. (2) Close-up view of processshowing bacteria adhering to special receptors bytheir PAMPs. (3) Vacuole is formed around bacteriaduring engulfment. (4) Phagosome digestive vacuoleresults. (5) Lysosomes fuse with phagosome, forminga phagolysosome. (6) Enzymes and toxic oxygenproducts kill and digest bacteria. (7) Undigestedparticles are released.

Phagolysosome Formation and Killing In a short time, lysosomes migrate to the scene of the phagosome and fuse with it to form a phagolysosome. Other granules containing antimicrobial chemicals are released into the phagolysosome, forming a potent brew designed to poison and then dismantle the ingested material (figure 2). The destructiveness of phagocytosis is evident by the death of bacteria within 30 minutes after contacting this battery of antimicrobial substances.

Destruction and Elimination Systems Destructive chemicals await the microbes in the phagolysosome. The oxygendependent system, known as the respiratory burst or oxidative burst, elaborates products of oxygen metabolism called reactive oxygen intermediates (ROI). Myeloperoxidase, an enzyme found in granulocytes, forms halogen ions (OCl^–) that are strong oxidizing agents. Other products of oxygen metabolism such as hydrogen peroxide, the superoxide anion (O₂^–), activated or singlet oxygen (¹O^–), and the hydroxyl free radical (HO) separately and together have formidable killing power. This series of reactive oxygen products delivers a “knockout” punch necessary to kill aerobic pathogens such as fungi and many bacteria (see case file).

Other chemicals that come into play are the lactic acid, lysozyme, and nitric oxide (NO), a powerful mediator that kills bacteria and inhibits viral replication. Cationic proteins that injure bacterial cell membranes and a number of proteolytic and other hydrolytic enzymes complete the job. The bits of undigestible debris are released from the macrophage by exocytosis. Macrophages and dendritic cells use this system to process microbes for specific immune responses with lymphocytes.

Fig. 3. Phagocyte detection and signaling with toll-like receptors. Toll-like receptors (TLRs) span the membrane ofphagocytes and other cells of the immune system. When a moleculesuch as a PAMP on a particular pathogen is recognized by thisreceptor, the TLRs merge and bind the foreign molecule. This inducesproduction of chemicals and triggers engulfment.

Дата добавления: 2015-06-04