Phagocytosis- definition, mechanism, steps with example

Phagocytosis is a type of endocytosis, which is the process of cells taking in materials from their surroundings by forming vesicles or vacuoles. Phagocytosis specifically refers to the ingestion of large particles, such as bacteria, viruses, fungi, cell debris, or foreign substances, that are too big to be transported by other means. Phagocytosis is an important mechanism of innate immunity, which is the first line of defense against infections and tissue damage. Phagocytosis helps to eliminate pathogens and clear away dead or damaged cells from the body.

Phagocytosis is a process by which cells ingest large particles (> 0.5 micrometers) into membrane-bound vesicles called phagosomes, which are then targeted to the lysosomes for enzymatic degradation. Phagocytosis can be divided into four main steps: recognition, engulfment, fusion, and digestion.

Recognition

Recognition is the first step of phagocytosis, in which the cell identifies and binds to the target particle. Recognition can be mediated by various receptors on the cell surface, such as complement receptors (CRs), Fc receptors (FcRs), scavenger receptors (SRs), toll-like receptors (TLRs), and lectin receptors. These receptors can recognize different types of molecules on the surface of the particle, such as antibodies, complement proteins, lipopolysaccharides, mannose, and other sugars. Recognition can also be enhanced by opsonization, which is the coating of the particle with serum proteins that facilitate its binding to the receptors.

Engulfment

Engulfment is the second step of phagocytosis, in which the cell extends its plasma membrane around the particle and forms a phagosome. Engulfment is driven by actin polymerization and depolymerization, which generate forces that push and pull the membrane around the particle. Engulfment also involves various proteins that regulate the membrane dynamics, such as phosphoinositides, Rho GTPases, WASP family proteins, and Arp2/3 complex.

Fusion

Fusion is the third step of phagocytosis, in which the phagosome fuses with a lysosome to form a phagolysosome. Fusion is mediated by various proteins that regulate the membrane trafficking and fusion, such as Rab GTPases, SNAREs, tethering factors, and calcium. Fusion allows the delivery of lysosomal enzymes and other molecules into the phagolysosome, where they can degrade the particle.

Digestion

Digestion is the final step of phagocytosis, in which the particle is killed and digested by various mechanisms. Digestion can involve oxygen-dependent and oxygen-independent mechanisms. Oxygen-dependent mechanisms involve the production of reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, and hydroxyl radical, by a complex of proteins called NADPH oxidase or NOX. ROS can damage various biological molecules, such as proteins, lipids, and DNA. Oxygen-independent mechanisms involve various antimicrobial molecules that are present in the lysosomes or secreted by the cell, such as proteases, lysozyme, defensins, lactoferrin, and nitric oxide. Digestion results in the breakdown of the particle into smaller fragments that can be released from the cell or recycled for further use.

Destruction of microbes through oxygen radicals, nitric oxide, anti-microbial proteins and peptides, binding proteins and hydrogen ion transport

Once the bacterium is engulfed by the phagocyte, it is enclosed in a membrane-bound vesicle called a phagosome. The phagosome then fuses with a lysosome, forming a phagolysosome. The lysosome contains various enzymes and substances that can kill and degrade the bacterium. Some of the main factors involved in the destruction of microbes are:

• Oxygen radicals: The phagocyte oxidase complex in the phagolysosome membrane generates reactive oxygen species (ROS) such as superoxide anion (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (OH-). These ROS can damage the bacterial cell wall, membrane, DNA, and proteins. The production of ROS is also known as the respiratory burst.
• Nitric oxide: The inducible nitric oxide synthase (iNOS) in the phagocyte produces nitric oxide (NO), a reactive nitrogen species (RNS) that can react with ROS to form peroxynitrite (ONOO-), a potent oxidant. NO can also inhibit bacterial enzymes and interfere with iron metabolism.
• Anti-microbial proteins: The lysosome contains various proteases that can degrade bacterial proteins. One of them is elastase, which has a broad spectrum of activity against different bacteria. Another one is lysozyme, which can break down the peptidoglycan layer of gram-positive bacteria.
• Anti-microbial peptides: The phagocyte also secretes small peptides that can disrupt the bacterial membrane. One example is defensins, which are cationic peptides that can insert into the membrane and form pores. Other examples are cathelicidins and histatins.
• Binding proteins: The phagocyte also deprives the bacterium of essential nutrients by binding them with specific proteins. One example is lactoferrin, which binds iron ions and prevents bacterial growth. Another example is transcobalamin II, which binds vitamin B12 and inhibits bacterial metabolism.
• Hydrogen ion transport: The phagocyte oxidase complex also pumps hydrogen ions (H+) into the phagolysosome, lowering its pH. This creates an acidic environment that can kill some bacteria and activate some lysosomal enzymes.

These factors work together to destroy the bacterium within the phagolysosome. The digested products are then released from the cell or presented to other immune cells for further recognition and response.

Cytokines are small proteins that are released by cells and act as messengers to coordinate the immune response. They can have various effects, such as stimulating or inhibiting the proliferation, differentiation, activation, migration, and survival of immune cells. They can also modulate the expression of receptors, enzymes, adhesion molecules, and other proteins on the cell surface or inside the cell.

Cytokines are produced by different types of cells involved in phagocytosis, such as neutrophils, macrophages, dendritic cells, and B lymphocytes. They can act in an autocrine manner (on the same cell that produces them), a paracrine manner (on nearby cells), or an endocrine manner (on distant cells).

Some examples of cytokines that are involved in phagocytosis are:

• Interleukin-1 (IL-1): This cytokine is produced by macrophages and dendritic cells after phagocytosis of bacteria. It stimulates the production of acute phase proteins by the liver, such as C-reactive protein (CRP) and complement components. It also induces fever and activates endothelial cells to express adhesion molecules and secrete chemokines that attract more immune cells to the site of infection.
• Interleukin-6 (IL-6): This cytokine is also produced by macrophages and dendritic cells after phagocytosis of bacteria. It enhances the production of acute phase proteins by the liver and stimulates the differentiation of B lymphocytes into plasma cells that secrete antibodies. It also promotes the growth and survival of neutrophils and regulates their apoptosis.
• Interleukin-8 (IL-8): This cytokine is produced by macrophages, neutrophils, and epithelial cells in response to bacterial infection. It is a potent chemokine that attracts more neutrophils and other phagocytes to the site of infection. It also activates neutrophils to increase their phagocytic activity and release of reactive oxygen species.
• Interleukin-12 (IL-12): This cytokine is produced by macrophages and dendritic cells after phagocytosis of bacteria. It stimulates the differentiation of naive T lymphocytes into Th1 cells that secrete interferon-gamma (IFN-gamma). IFN-gamma activates macrophages to increase their phagocytic activity and release of nitric oxide. It also enhances the expression of major histocompatibility complex (MHC) class II molecules on antigen-presenting cells, which facilitates the presentation of bacterial antigens to T lymphocytes.
• Tumor necrosis factor-alpha (TNF-alpha): This cytokine is produced by macrophages and neutrophils after phagocytosis of bacteria. It induces inflammation by activating endothelial cells to express adhesion molecules and secrete chemokines. It also increases the permeability of blood vessels, which allows more immune cells and fluid to enter the infected tissue. It also stimulates the production of other cytokines, such as IL-1 and IL-6.

These are some of the main cytokines that play a role in phagocytosis and immune response. However, there are many other cytokines that have diverse functions in regulating the immune system. Cytokines can act synergistically or antagonistically with each other, depending on the context and concentration. Therefore, the balance between pro-inflammatory and anti-inflammatory cytokines is crucial for maintaining homeostasis and preventing excessive tissue damage or chronic inflammation.

Phagocytosis is a process by which cells ingest large particles (> 0.5 micrometers) into membrane-bound vesicles called phagosomes, which are then targeted to the lysosomes for enzymatic degradation. Phagocytosis is an important mechanism of innate immunity, as it helps to eliminate pathogens and foreign materials from the body. Several types of cells in the immune system can perform phagocytosis, each with different roles and functions.

• Neutrophils: Neutrophils are the most abundant type of white blood cells in the blood, and they are the first responders to infection and inflammation. They quickly migrate to the site of infection and phagocytize bacteria, fungi, and other microorganisms. Neutrophils have a short lifespan and undergo apoptosis after killing the pathogens. They also release cytokines and chemokines that attract other immune cells and modulate the inflammatory response.
• Macrophages: Macrophages are derived from monocytes that differentiate in various tissues. They are long-lived cells that can phagocytize a wide range of particles, including bacteria, viruses, fungi, protozoa, apoptotic cells, and cellular debris. Macrophages also act as antigen-presenting cells (APCs), as they process and present antigens to T lymphocytes and initiate adaptive immunity. Macrophages secrete various cytokines and growth factors that regulate inflammation, wound healing, and tissue repair.
• Dendritic Cells: Dendritic cells are specialized APCs that capture antigens from the extracellular environment and transport them to the lymph nodes, where they present them to naive T lymphocytes. Dendritic cells can phagocytize bacteria, viruses, and other antigens, but their main function is to activate T cells and induce specific immune responses. Dendritic cells also secrete cytokines that influence the differentiation and polarization of T cells.
• B Lymphocytes: B lymphocytes are the cells that produce antibodies in response to antigens. B lymphocytes can also phagocytize antigens that are coated with antibodies or complement components (opsonized antigens). This process enhances the activation of B cells and facilitates their differentiation into plasma cells or memory B cells. Phagocytosis by B lymphocytes is important for humoral immunity and immunological memory.

These are the main types of cells involved in phagocytosis. Each type has a distinct role and function in innate and adaptive immunity. Phagocytosis is a vital process that helps to clear infections and maintain homeostasis in the body.

Phagocytosis of a bacterium involves the following steps:

1. Recognition and attachment: The phagocyte recognizes the bacterium as a foreign particle and binds to it through specific receptors on its surface. These receptors can recognize molecules on the bacterial surface such as lipopolysaccharide (LPS), peptidoglycan, flagella, or capsule. Alternatively, the bacterium can be opsonized by antibodies or complement proteins that coat its surface and enhance its recognition by the phagocyte.
2. Engulfment: The phagocyte extends its plasma membrane around the bacterium and forms pseudopodia that surround and enclose it. The pseudopodia fuse at their tips and seal off the bacterium in a membrane-bound vesicle called a phagosome.
3. Fusion with lysosome: The phagosome moves towards the center of the phagocyte and fuses with a lysosome, which contains various hydrolytic enzymes and antimicrobial substances. The fusion creates a phagolysosome, where the bacterium is exposed to a harsh environment that kills and degrades it.
4. Degradation: The lysosomal enzymes break down the bacterial components into smaller molecules that can be used by the phagocyte or released into the extracellular space. Some of these molecules include peptides, sugars, nucleotides, and fatty acids. The degradation also generates reactive oxygen species (ROS) and reactive nitrogen species (RNS) that further damage the bacterium and its DNA.
5. Exocytosis: The phagolysosome fuses with the plasma membrane and releases its contents into the extracellular space. This process eliminates any remaining bacterial fragments and prevents their accumulation inside the phagocyte. The exocytosis also allows the presentation of bacterial antigens to other immune cells that can initiate a specific immune response.

The following image illustrates the steps in the phagocytosis of a bacterium:

Source: Wikimedia Commons

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