Phagocytosis

Jan Verhoef, Eijkman-Winkler Institute for Microbiology, Infectious Diseases & Inflammation, University Hospital Utrecht, Utrecht, The Netherlands

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

Phagocytosis by phagocytic cells is a crucial part of the host defense against invading microorganisms once the outer epithelial surface of the body has been breached (Figures 1 and 2). The most important cell types involved are polymorphonuclear leukocytes (PMNs) and mononuclear phagocytes (MNs; monocytes and macrophages), both of which are derived from precursor cells in the bone marrow. PMNs are released into the circulation in vast numbers in a fully differentiated state, with a half-life in the bloodstream of only about 6 h. The turnover rate of these cells is enormous; each day about 10" PMNs disappear from the bloodstream to be replaced by equal numbers from the bone marrow. Monocytes are capable of further differentiation. After migration from the blood to tissues (diapedesis), they become macrophages of the mononuclear phagocytic system. These fixed macrophages are strategically placed to defend the body against invading microorganisms by lining blood sinusoids in the liver, spleen, bone marrow, adrenals, etc.

After invasion of the tissues by microorganisms, circulating PMNs become activated. This process is triggered by bacterial cell wall products (e.g. lipo-polysaccharides, peptidoglycan, etc.), cytokines (e.g. interleukin 1, IL-1) and many other molecules (e.g. platelet-activating factor). Activated PMNs leave the bloodstream by adhering to endothelial cells and moving through the endothelial barrier to the site of the infection. This process of migration is called chemotaxis and is defined as cell movement in one direction in response to an agent (chemoattractant) (Figure 3).

Neutrophil chemotaxis requires the binding of chemoattractants to specific membrane receptors. Chemoattractants include bacterial products, activated complement factors (C5a), arachidonic acid metabolites (LTB4), and cytokines such as IL-1, IL-8. These bind to G proteins of PMNs, leading to signal transmission to the interior of the cell which in turn leads to activation of the PMN and thus expression of adhesion molecules.

The first event during chemotaxis is the slowing or margination of the circulating leukocytes within the venule where the white cells are loosely tethered to the vessel wall and roll along the surface of the endothelium. After rolling, many neutrophils firmly adhere to the endothelial cell surface and become

Figure 1 Polymorphonuclear leukocyte in the process of phagocytosing Escherichia coli.

Blood vessel activation with PMN adherence endothelial endothelial

Blood vessel activation with PMN adherence

Figure 2 Processes involved in phagocytosis of bacteria by polymorphonuclear leukocytes. (Reproduced with permission from Verhoef and Visser (1993) In: Abramson and Wheeler (eds) The Neutrophil pp 109-137. Oxford: IRL Press.)

diapedesis chemotaxis opsonization attachment ingestion killing digestion

Figure 2 Processes involved in phagocytosis of bacteria by polymorphonuclear leukocytes. (Reproduced with permission from Verhoef and Visser (1993) In: Abramson and Wheeler (eds) The Neutrophil pp 109-137. Oxford: IRL Press.)

activated, changing from a spherical configuration to a flattened shape (Figure 3). During tethering, a family of three lectin-like carbohydrate-binding molecules called L-selectin, E-selectin and P-selectin arc activated. L-selectins are expressed on most leukocytes, while E- and P-selectins are expressed by endothelial cells. Selectins promote leukocyte rolling and recognize specific carbohydrates on either leukocytes

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Plum

/P-sefectin E-selectin (early) (later)

Endothel lu m

1CAM-2 Endothelium

Figure 3 Process of chemotaxis. Neutrophils (PMN) are activated, adhere to the endothelial surface, role over the surface, spread and move through the endothelial cell layer. (Reproduced with permission from Verhoef and Visser (1993) In: Abramson and Wheeler (eds) The Neutrophil, pp 109-137. Oxford: IRL Press.)

/P-sefectin E-selectin (early) (later)

Endothel lu m

1CAM-2 Endothelium igG

classical pathway of complement activation igG

classical pathway of complement activation

alternative pathway of complement

Figure 4 Opsonization of bacteria.

alternative pathway of complement

Figure 4 Opsonization of bacteria.

Figure 3 Process of chemotaxis. Neutrophils (PMN) are activated, adhere to the endothelial surface, role over the surface, spread and move through the endothelial cell layer. (Reproduced with permission from Verhoef and Visser (1993) In: Abramson and Wheeler (eds) The Neutrophil, pp 109-137. Oxford: IRL Press.)

or the endothelium (L-selectin), which leads to tethering of the leukocytes. Adhesion by selectins is not strong enough to stop the flow of leukocytes completely. Adhesion molecules called integrins are responsible for the firm adhesion of leukocytes to endothelium. Activation of the integrins stops the flow of leukocytes.

Many of the activators (triggers) needed for the adhesion of PMNs to endothelial cells and subsequent chemotaxis are produced by the endothelial cells themselves, and by monocytes, bacteria, etc. There is growing evidence that the neutrophil itself is also able to produce chemotactic factors and activators.

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