Intracellular transport
Intracellular transport

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Intracellular transport

6.4 Phagocytosis

Phagocytosis in vertebrates and invertebrates is conducted primarily by specialised cells such as macrophages, monocytes and neutrophils, which internalise large pathogens such as bacteria and yeast, or large debris, such as the remnants of dead cells or arterial deposits of fat. Material that has been internalised by phagocytosis forms a phagocytic vacuole (phagosome) and will eventually be degraded when lysosomes fuse with the phagosome to form a phagolysosome, releasing their digestive enzymes into the vacuole (Figure 37). However, the way that a phagocyte responds to phagocytosed material depends very much on the nature of the material and the way in which it is recognised before internalisation. For example, bacteria are recognised by the phagocyte as potentially dangerous and they trigger the cell to direct cytotoxic molecules against the internalised bacteria, before digestion in the phagolysosome. Phagocytosis by this pathway activates the phagocyte, which releases cytokines that signal local inflammation. In contrast, debris from cells that have died as part of the normal process of cell turnover, are phagocytosed and degraded, but do not induce the release of cytotoxic molecules, nor do they induce inflammation.

Figure 37 Electron micrograph of a phagocyte (a neutrophil) that has internalised a yeast cell. The yeast cell is enclosed within a membrane-bound phagosome, and lysosomes (arrowed) are fusing with the phagosome to form a phagolysosome.

Let us look first at the phagocytosis of apoptotic cells. A molecule that is essential for the successful endocytosis of dying cells is phosphatidylserine.

Exposure of phosphatidylserine occurs on the outer leaflet of the plasma membrane when cells die by apoptosis. Macrophages have a conserved receptor for phosphatidylserine as well as a number of ‘scavenger receptors’, which can bind to a variety of other cellular debris. These receptors promote the uptake of dead cells, but crucially, phagocytosis of such debris is associated with the release of cytokines that suppress inflammation. Since apoptosis is a normal physiological process, there is no requirement for the macrophage to signal an inflammatory reaction.

Contrast this with the phagocytosis of pathogens, which are recognised by binding to Fc receptors (Antibody receptors) and C3b receptors. (Antibody and C3b are immune system molecules that specifically bind to foreign material.) Some classes of Fc receptors have intracellular domains, which become phosphorylated when the receptor is ligated with antibody. As a consequence, material phagocytosed by these receptors activates the cell and causes it to generate reactive oxidative compounds (e.g. hydrogen peroxide) in the phagosome (Figure 38).

Figure 38 Phagocytosis of apoptotic cell debris (left) and pathogens (right) activates different responses in a macrophage. Apoptotic cells taken up by scavenger receptors and a proposed phosphatidylserine receptor are directed to lysosomes, and cause the cell to release cytokines TGFβ and IL-10 which tend to damp down inflammatory reactions. Pathogens such as a bacterium are tagged by antibody and C3b which bind to receptors, which promote internalisation, but also induce the secretion of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) into the phagosomes, to damage or kill the pathogen. This process induces the release of proinflammatory cytokines, such as tumour necrosis factor (TNFα). Killed pathogens are directed to the lysosome for degradation.

Phagocytosis activates GTPases of the Rho family, which cause reorganisation of the cytoskeleton as the cell extends processes around the receptor-bound material. The precise way in which this occurs depends on the receptors to which the material has been bound. For example, binding to the Fc receptor will activate a signalling cascade involving activation of Cdc42 and Rac, which causes actin assembly and the formation of cell-surface extensions that close up around the antibody-coated pathogen to engulf it. In other cases, spacious phagosomes may form where the cell extends pseudopodia that eventually fall back on the membrane to enclose the particle and a volume of extracellular fluid. Different receptors appear to trigger phagocytosis by related mechanisms but involving different GTPases.

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