Phagocytosis (from Ancient Greek φαγεῖν (phagein) , meaning 'to eat', and κύτος, (kytos) , meaning 'cell') is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm) , giving rise to an internal compartment called the phagosome. It is one type of endocytosis pinocytosis.
In a multicellular organism's immune system, phagocytosis is a major mechanism used to remove pathogens and cell debris. The ingested material is then digested in the phagosome. Bacteria, dead tissue cells, and small mineral particles are all examples of objects that may be phagocytized. Some protozoa use phagocytosis as means to obtain nutrients.
Phagocytosis is one of the main mechanisms of the innate immune defense. It is one of the first processes responding to infection, and is also one of the initiating branches of an adaptive immune response. Although most cells are capable of phagocytosis, some cell types perform it as part of their main function. These are called 'professional phagocytes.' Phagocytosis is old in evolutionary terms, being present even in invertebrates.
Neutrophils, macrophages, monocytes, dendritic cells, osteoclasts and eosinophils can be classified as professional phagocytes. The first three have the greatest role in immune response to most infections.
The role of neutrophils is patrolling the bloodstream and rapid migration to the tissues in large numbers only in case of infection. There they have direct microbicidal effect by phagocytosis. After ingestion, neutrophils are efficient in intracellular killing of pathogens. Neutrophils phagocytose mainly via the Fcγ receptors and complement receptors 1 and 3. The microbicidal effect of neutrophils is due to a large repertoire of molecules present in pre-formed granules. Enzymes and other molecules prepared in these granules are proteases, such as collagenase, gelatinase or serine proteases, myeloperoxidase, lactoferrin and antibiotic proteins. Degranulation of these into the phagosome, accompanied by high reactive oxygen species production (oxidative burst) is highly microbicidal.
Monocytes, and the macrophages that mature from them, leave blood circulation to migrate through tissues. There they are resident cells and form a resting barrier. Macrophages initiate phagocytosis by mannose receptors, scavenger receptors, Fcγ receptors and complement receptors 1, 3 and 4. Macrophages are long-lived and can continue phagocytosis by forming new lysosomes.
Dendritic cells also reside in tissues and ingest pathogens by phagocytosis. Their role is not killing or clearance of microbes, but rather breaking them down for antigen presentation to the cells of the adaptive immune system.
Receptors for phagocytosis can be divided into two categories by recognised molecules. The first, opsonic receptors, are dependent on opsonins. Among these are receptors that recognise the Fc part of bound IgG antibodies, deposited complement or receptors, that recognise other opsonins of cell or plasma origin. Non-opsonic receptors include lectin-type receptors, Dectin receptor, or scavenger receptors. Some phagocytic pathways require a second signal from pattern recognition receptors (PRRs) activated by attachment to pathogen-associated molecular patterns (PAMPS), which leads to NF-κB activation.
Fcγ receptors recognise IgG coated targets. The main recognised part is the Fc fragment. The molecule of the receptor contain an intracellular ITAM domain or associates with an ITAM-containing adaptor molecule. ITAM domains transduce the signal from the surface of the phagocyte to the nucleus. For example activating receptors of human macrophages are FcγRI, FcγRIIA, and FcγRIII. Fcγ receptor mediated phagocytosis includes formation of protrusions of the cell called a 'phagocytic cup' and activates an oxidative burst in neutrophils.
These receptors recognise targets coated in C3b, C4b and C3bi from plasma complement. The extracellular domain of the receptors contains a lectin-like complement-binding domain. Recognition by complement receptors is not enough to cause internalisation without additional signals. In macrophages, the CR1, CR3 and CR4 are responsible for recognition of targets. Complement coated targets are internalised by 'sinking' into the phagocyte membrane, without any protrusions.
Mannose and other pathogen-associated sugars, such as fucose, are recognised by the mannose receptor. Eight lectin-like domains form the extracellular part of the receptor. The ingestion mediated by the mannose receptor is distinct in molecular mechanisms from Fcγ receptor or complement receptor mediated phagocytosis.
Engulfment of material is facilitated by the actin-myosin contractile system. The phagosome is the organelle formed by phagocytosis of material. It then moves toward the centrosome of the phagocyte and is fused with lysosomes, forming a phagolysosome and leading to degradation. Progressively, the phagolysosome is acidified, activating degradative enzymes.
Degradation can be oxygen-dependent or oxygen-independent.
Following apoptosis, the dying cells need to be taken up into the surrounding tissues by macrophages in a process called efferocytosis. One of the features of an apoptotic cell is the presentation of a variety of intracellular molecules on the cell surface, such as calreticulin, phosphatidylserine (from the inner layer of the plasma membrane), annexin A1, oxidised LDL and altered glycans. These molecules are recognised by receptors on the cell surface of the macrophage such as the phosphatidylserine receptor or by soluble (free-floating) receptors such as thrombospondin 1, GAS6, and MFGE8, which themselves then bind to other receptors on the macrophage such as CD36 and alpha-v beta-3 integrin. Defects in apoptotic cell clearance is usually associated with impaired phagocytosis of macrophages. Accumulation of apoptotic cell remnants often causes autoimmune disorders; thus pharmacological potentiation of phagocytosis has a medical potential in treatment of certain forms of autoimmune disorders.
In many protists, phagocytosis is used as a means of feeding, providing part or all of their nourishment. This is called phagotrophic nutrition, distinguished from osmotrophic nutrition which takes place by absorption.
As in phagocytic immune cells, the resulting phagosome may be merged with lysosomes containing digestive enzymes, forming a phagolysosome. The food particles will then be digested, and the released nutrients are diffused or transported into the cytosol for use in other metabolic processes.
Agglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare (glueing to).
Agglutination is the process that occurs if an antigen is mixed with its corresponding antibody called isoagglutinin. This term is commonly used in blood grouping.
This occurs in biology in two main examples:
The clumping of cells such as bacteria or red blood cells in the presence of an antibody or complement. The antibody or other molecule binds multiple particles and joins them, creating a large complex. This increases the efficacy of microbial elimination by phagocytosis as large clumps of bacteria can be eliminated in one pass, versus the elimination of single microbial antigens.
When people are given blood transfusions of the wrong blood group, the antibodies react with the incorrectly transfused blood group and as a result, the erythrocytes clump up and stick together causing them to agglutinate. The coalescing of small particles that are suspended in a solution; these larger masses are then (usually) precipitated.CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.CD47 is involved in a range of cellular processes, including apoptosis, proliferation, adhesion, and migration. Furthermore, it plays a key role in immune and angiogenic responses. CD47 is ubiquitously expressed in human cells and has been found to be overexpressed in many different tumor cells. Expression in equine cutaneous tumors has been reported as well.CD93
CD93 (Cluster of Differentiation 93) is a protein that in humans is encoded by the CD93 gene. CD93 is a C-type lectin transmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defense.Chédiak–Higashi syndrome
Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein, which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, albinism and peripheral neuropathy.Collodictyonidae
Collodictyonidae (also Diphylleidae) is a group of aquatic, unicellular eukaryotic organisms with two to four terminal flagella. They feed by phagocytosis, ingesting other unicellular organisms like algae and bacteria. The most remarkable fact of this clade is its uncertain position in the tree of life. A recent phylogenomic analysis places it either as sister group of the excavate protist Malawimonas or as sister group of the Bikonta clade, although both positions received considerably low branch support values. This means that Collodictyonidae is somewhere near the root of the Eukaryote tree, probably close to the unikont–bikont bifurcation.Cytostome
A cytostome (from cyto-, cell and stome-, mouth) or cell mouth is a part of a cell specialized for phagocytosis, usually in the form of a microtubule-supported funnel or groove. Food is directed into the cytostome, and sealed into vacuoles.
Only certain groups of protozoa, such as the Ciliophora and Excavata, have cytostomes. An example is Balantidium coli, a ciliate. In other protozoa, and in cells from multicellular organisms, phagocytosis takes place at any point on the cell or feeding takes place by absorption.Endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. Endocytosis includes pinocytosis (cell drinking) and phagocytosis (cell eating). It is a form of active transport.FCGR2B
Fc fragment of IgG receptor IIb (coded by FCGR2B gene) is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma (IgG). FCGR2B participates in the phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes.Fc receptor
An Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system.
Its name is derived from its binding specificity for a part of an antibody known as the Fc (Fragment, crystallizable) region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.Integrin alpha M
Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily (or leukocyte) integrins.αMβ2 is expressed on the surface of many leukocytes involved in the innate immune system, including monocytes, granulocytes, macrophages, and natural killer cells. It mediates inflammation by regulating leukocyte adhesion and migration and has been implicated in several immune processes such as phagocytosis, cell-mediated cytotoxicity, chemotaxis and cellular activation. It is involved in the complement system due to its capacity to bind inactivated complement component 3b (iC3b). The ITGAM (alpha) subunit of integrin αMβ2 is directly involved in causing the adhesion and spreading of cells but cannot mediate cellular migration without the presence of the β2 (CD18) subunit.In genomewide association studies, single nucleotide polymorphisms in ITGAM had the strongest association with systemic lupus erythematosus, with an odds ratio of 1.65 for the T allele of rs9888739 and lupus.In histopathology, immunohistochemistry with antibodies against CD11B is frequently used to identify macrophages and microglia.Ischemic cell death
Ischemic cell death, or oncosis, is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the Endoplasmic Reticulum and Golgi, mitochondrial condensation, chromatin clumping, and cytoplasmic bleb formation. Oncosis refers to a series of cellular reactions following injury that precedes cell death. The process of oncosis is divided into three stages. First, the cell becomes committed to oncosis as a result of damage incurred to the plasma membrane through toxicity or ischemia, resulting in the leak of ions and water due to ATP depletion. The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. Stage two the reversibility threshold for the cell is passed and it becomes committed to cell death. During this stage the membrane becomes abnormally permeable to trypan blue and propidium iodide, indicating membrane compromise. The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response.Macrophage
Macrophages (Greek: big eaters, from Greek μακρός (makrós) = large, φαγείν (phageín) = to eat) are a type of white blood cell, of the immune system, that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells on its surface in a process called phagocytosis.
These large phagocytes are found in essentially all tissues, where they patrol for potential pathogens by amoeboid movement. They take various forms (with various names) throughout the body (e.g., histiocytes, Kupffer cells, alveolar macrophages, microglia, and others), but all are part of the mononuclear phagocyte system. Besides phagocytosis, they play a critical role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes. For example, they are important as antigen presenters to T cells. In humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections.
Beyond increasing inflammation and stimulating the immune system, macrophages also play an important anti-inflammatory role and can decrease immune reactions through the release of cytokines. Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages. This difference is reflected in their metabolism; M1 macrophages have the unique ability to metabolize arginine to the "killer" molecule nitric oxide, whereas rodent M2 macrophages have the unique ability to metabolize arginine to the "repair" molecule ornithine. However, this dichotomy has been recently questioned as further complexity has been discovered.
Human macrophages are about 21 micrometres (0.00083 in) in diameter and are produced by the differentiation of monocytes in tissues. They can be identified using flow cytometry or immunohistochemical staining by their specific expression of proteins such as CD14, CD40, CD11b, CD64, F4/80 (mice)/EMR1 (human), lysozyme M, MAC-1/MAC-3 and CD68.Macrophages were first discovered by Élie Metchnikoff, a Russian zoologist, in 1884.Macrophage-1 antigen
Macrophage-1 antigen (or integrin αMβ2 or macrophage integrin or Mac-1) is a complement receptor ("CR3") consisting of CD11b (integrin αM) and CD18 (integrin β2).It binds to iC3b and C4b.Mannose receptor
The mannose receptor (Cluster of Differentiation 206, CD206) is a C-type lectin primarily present on the surface of macrophages, immature dendritic cells and liver sinusoidal endothelial cells, but is also expressed on the surface of skin cells such as human dermal fibroblasts and keratinocytes. It is the first member of a family of endocytic receptors that includes Endo180 (CD280), M-type PLA2R, and DEC-205 (CD205).The receptor recognises terminal mannose, N-acetylglucosamine and fucose residues on glycans attached to proteins found on the surface of some microorganisms, playing a role in both the innate and adaptive immune systems. Additional functions include clearance of glycoproteins from the circulation, including sulphated glycoprotein hormones and glycoproteins released in response to pathological events. The mannose receptor recycles continuously between the plasma membrane and endosomal compartments in a clathrin-dependent manner.Neutrophil
Neutrophils (also known as neutrocytes) are the most abundant type of granulocytes and the most abundant (60% to 70%) type of white blood cells in most mammals. They form an essential part of the innate immune system. Their functions vary in different animals.They are formed from stem cells in the bone marrow and differentiated into subpopulations of neutrophil-killers and neutrophil-cagers. They are short-lived and highly motile, or mobile, as they can enter parts of tissue where other cells/molecules cannot. Neutrophils may be subdivided into segmented neutrophils and banded neutrophils (or bands). They form part of the polymorphonuclear cells family (PMNs) together with basophils and eosinophils.The name neutrophil derives from staining characteristics on hematoxylin and eosin (H&E) histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain a nucleus divided into 2–5 lobes.
Neutrophils are a type of phagocyte and are normally found in the bloodstream. During the beginning (acute) phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation. They migrate through the blood vessels, then through interstitial tissue, following chemical signals such as Interleukin-8 (IL-8), C5a, fMLP, Leukotriene B4 and H2O2 in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance.Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cells.Opsonin
An opsonin (from the Greek opsōneîn, to prepare for eating) is any molecule that enhances phagocytosis by marking an antigen for an immune response or marking dead cells for recycling (i.e., causes the phagocyte to "relish" the marked cell). Opson in ancient Greece referred to the delicious side-dish of any meal, versus the sitos, or the staple of the meal.
Opsonization (also, opsonisation) is the molecular mechanism whereby molecules, microbes, or apoptotic cells are chemically modified to have a stronger attraction to the cell surface receptors on phagocytes and NK cells. With the antigen coated in opsonins, binding to immune cells is greatly enhanced. Opsonization also mediates phagocytosis via signal cascades from cell surface receptors.Opsonins aid the immune system in a number of ways. In a healthy individual, they mark dead and dying self cells for clearance by macrophages and neutrophils, activate complement proteins, and target cells for destruction through the action of natural killer (NK) cells.Phagocyte
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.Phagocytes of humans and other animals are called "professional" or "non-professional" depending on how effective they are at phagocytosis. The professional phagocytes include many types of white blood cells (such as neutrophils, monocytes, macrophages, mast cells, and dendritic cells). The main difference between professional and non-professional phagocytes is that the professional phagocytes have molecules called receptors on their surfaces that can detect harmful objects, such as bacteria, that are not normally found in the body. Phagocytes are crucial in fighting infections, as well as in maintaining healthy tissues by removing dead and dying cells that have reached the end of their lifespan.During an infection, chemical signals attract phagocytes to places where the pathogen has invaded the body. These chemicals may come from bacteria or from other phagocytes already present. The phagocytes move by a method called chemotaxis. When phagocytes come into contact with bacteria, the receptors on the phagocyte's surface will bind to them. This binding will lead to the engulfing of the bacteria by the phagocyte. Some phagocytes kill the ingested pathogen with oxidants and nitric oxide. After phagocytosis, macrophages and dendritic cells can also participate in antigen presentation, a process in which a phagocyte moves parts of the ingested material back to its surface. This material is then displayed to other cells of the immune system. Some phagocytes then travel to the body's lymph nodes and display the material to white blood cells called lymphocytes. This process is important in building immunity, and many pathogens have evolved methods to evade attacks by phagocytes.Phagosome
In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs). A phagosome is formed by the fusion of the cell membrane around a microorganism, a senescent cell or an apoptotic cell. Phagosomes have membrane-bound proteins to recruit and fuse with lysosomes to form mature phagolysosomes. The lysosomes contain hydrolytic enzymes and reactive oxygen species (ROS) which kill and digest the pathogens. Phagosomes can also form in non-professional phagocytes, but they can only engulf a smaller range of particles, and do not contain ROS. The useful materials (e.g. amino acids) from the digested particles are moved into the cytosol, and waste is removed by exocytosis. Phagosome formation is crucial for tissue homeostasis and both innate and adaptive host defense against pathogens.
However, some bacteria can exploit phagocytosis as an invasion strategy. They either reproduce inside of the phagolysosome (e.g. Coxiella spp.) or escape into the cytoplasm before the phagosome fuses with the lysosome (e.g. Rickettsia spp.).
Many Mycobacteria, including Mycobacterium tuberculosis
and Mycobacterium avium paratuberculosis
, can manipulate the host macrophage to prevent lysosomes from fusing with phagosomes and creating mature phagolysosomes. Such incomplete maturation of the phagosome maintains an environment favorable to the pathogens inside it
.Signal-regulatory protein alpha
Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.
SIRPα acts as inhibitory receptor and interacts with a broadly expressed transmembrane protein CD47 also called the "don´t eat me" signal. This interaction negatively controls effector function of innate immune cells such as host cell phagocytosis. SIRPα diffuses laterally on the macrophage membrane and accumulates at a phagocytic synapse to bind CD47 and signal 'self', which inhibits the cytoskeleton-intensive process of phagocytosis by the macrophage. This is analogous to the self signals provided by MHC class I molecules to NK cells via Ig-like or Ly49 receptors. NB. Protein shown to the right is CD47 not SIRP α.
Mechanisms for chemical transport through biological membranes