Phagocytosis

Phagocytosis is the ability of certain cell types to ingest large particulate matter. To accomplish this, the cells must deform their bodies to capture the particles and then internalise them. All cells are capable of internalising material from their external environment. Biologists refer to this process as endocytosis (endo = inner; cyto = cell). Cells are capable of 'drinking'. This is called pinocytosis and describes the process by which cells internalise small quantities of aqueous, extracellular media. The media is contained in small endocytic vesicles and small, dissolved molecules can be transported into the cell by this route. It is generally believed that all cells are capable of pinocytosis. Phagocytosis, on the other hand, is carried out by specialised cell type. While pinocytosis does not require significant changes to a cell's shape, phagocytosis results in profound (albeit temporary) changes to a cell's shape. To change its shape, the cell must reorganise its cytoskeleton. The cytoskeleton is a protein framework that spans much of a cell's internal space. It consists of a number of different proteins that form the basic scaffolding within the cytoplasm (and organelles), as well as anchoring proteins and enzymes. Without the cytoskeleton, a cell will not have clearly defined morphologies. A lot of intracellular trafficking (e.g. movement of vesicles and organelles) relies on the the cytoskeleton.


Phagocytes have a flexible morphology and, under the microscope, these cells appear to crawl when moving from one point to the next. This is made possible by a flexible and dynamic cytoskeleton. In phagocytes, one type of cytoskeletalstructureis particularly dynamic. This is the actin cytoskeleton. The actin cytoskeleton is made up of a small, globular protein called actin. Individual actin proteins (monomers) can be rapidly assembled into long chains of actin filaments (polymers). It is analogous to threading beads to form a chain or assembling a wall with bricks. The polymerisation of actin is a reversible reaction, and hence, the actin polymer can be broken down. This assembly and disassembly of the actin cytoskeleton makes it dynamic. Other proteins in the cytoplasm can influence this process. Some proteins bind to the polymeric form of actin and stabilise it, thus greatly slowing down the disassembly process. In cells with fixed and rigid morphologies, the actin cytoskeleton is highly stable. Another group of cytoplasmic proteins speed up the disassembly of the cytoskeleton, thus converting the actin polymers into monomers. The monomers can then be reassembled into polymers elsewhere in the cell. Thus, the state of the actin cytoskeleton in a phagocyte is a balance between these two opposing forces.


One model of phagocytosis is that phagocytes are able to determine the locations of particles (e.g. food, bacteria) in the extracellularenvironment. The surfaces of phagocytes are studded with cell surface receptors to which target molecules (e.g. bacterial cell wall components) bind. The binding of the target molecules (also called ligands) to the receptors triggers intracellular signalling within the phagocyte. The signal activates cytoplasmic enzymes and other actin destabilising proteins (e.g. gelsolin). This results in the disassembly of the actin polymers. It is thought that the disassembly occurs at the distal point of the cell (ie the end of the cell thatfurthermostaway from ligand reception). The actin monomers formed as a result of this are pushed towards the 'front' of the cell by a process known as cytoplasmic streaming. Once there, the monomers reassemble into polymers. This causes that portion of the cell to extrude (towards the food source or bacteria). The polymers are them stabilised and the cytoplasm stream into this extruded area. The extrusion is called a pseudopodium. A single cell is capable of producing a number of pseudopodia simultaneously. By this means, the cell is able to 'crawl’.


Cells are constantly surveying their extracellular environment. Indeed, phagocytes are able to 'develop a sense of directionality'. They do so by detecting varying concentrations of ligands in their environment. For example, if there are bacterial cells in the vicinity of a phagocyte, the receptors on the surfaces of the phagocyte will bind to bacterial cell wall fragments in the extracellular medium. The intracellular signals generated within the phagocyte thenstabilisesthe phagocyte's pseudopodia that are closest to the 'highest concentration' of those cell wall fragments. The phagocyte continues to extend the pseudopodia in the direction of increasing concentrations of the cell wall fragments, until they come into contact with the bacterial cells. (Note: this type of movement towards or away from chemical signals is known as chemotaxis). The pseudopodia then wrap around the bacterial cells in a deathly embrace. The bacteria become trapped within vesicles (called endosomal vesicles or phagosomes). These phagosome move into the interior of the phagocyte, where they will fuse with other cytoplasmic vesicles (called lysosomes) that contain a cocktail of digestive enzymes. The bacterial cells are then broken down and useful components, such as amino acids, are pumped into the phagocyte's cytoplasm (where they add to the pool of the cell's amino acid reserves). Any unwanted material is eliminated from the phagocyte.


The abovementioned description is a very simplistic account of phagocytic cells. Phagocytosis is a highly regulated phenomenon and involves complex interactions within phagocytes, as well as between the phagocyte and its external environment (such as the external substrate). Numerous proteins link a phagocyte's cytoskeleton with proteins in the extracellular space. Indeed, then crawling cells do not crawl, but walk on 'stilts'. Within multicellular organisms, there are clearly defined 'railroad tracks and highways' with clear signage. In other words, phagocytes are capable of processing amultitudeof signals about their environment and thepresenceof potential threats or food sources in those environments.

Phagocytes are very efficient at ingesting particulate matter. Hence, although metazoans developed specialised organ systems for digestion, which made the nutritive roles of phagocytes redundant, their roles wereco-optedinto another physiological system - that of host defence. It is evident that that the immunological roles of these phagocytes was becoming very sophisticated and complex - they were being integrated into the many different layers of metazoan immune systems. For example, intercellular signalling via a range of secreted (soluble) mediators became a major evolutionary innovation. If a phagocyte encounters and ingests a bacterium within a multicellular organism, it is possible that the organism may be undergoing an infection. Hence, that phagocyte will alert other cells to the possibility of a bacterial infection. It does this by secreting signalling molecules, which 'activates' other phagocytes. This recruits phagocytes to the sites of infection. In vertebrates, the soluble mediators (e.g. cytokines and interleukins) form the nexus between the innate and adaptive arms of the immune system. These molecules are capable of activating the adaptive immune system. The receptors of the adaptive immune system recognise non-self determinants that are presented on the Major Histocompatibility Complex receptors. That triggers a signal transduction pathway to be activated within lymphocytes. However, the lymphocytes also require a second, exogenous signal: this is provided by the soluble mediators secreted by the phagocytes. Often, the Antigen Presenting Cells (cells which present foreign antigens on the MHC II receptors) of the adaptive immune system are phagocytes.

The roles of soluble mediators secreted by phagocytes within invertebrates, as well as the mechanisms by which they function, is not known.

However, there is evidence that unicellular phagocytes are capable of communicating via chemical signalling. For example, the social amoebae Dictyostelium discoideum often aggregate during times of scarce nutrition through folic acid signalling. In a spectacular series of cellular reactions, these cells aggregate and form multicellular structures (slug and fruiting bodies).

sham.nair@mq.edu.au
shamnair@gmail.com

Sham Nair 2014