In this article, I briefly explain phagocytosis, the process which abolishes pathogens.
Phagocytosis
Phagocytosis is simply a mechanism in which a white blood cell (phagocyte) envelops a foreign particle and annihilates it, thereafter discards the dead cells. In this process, the cell uses its plasma membrane to engulf the foreign particle, developing an internal compartment known as a phagosome.
In multicellular organisms, it is an important process to eliminate pathogens and cell debris. Pathogens that have pierced the epithelial barrier face the defense from phagocytic cells.
The main cell types, otherwise known as professional phagocytic cells carrying out phagocytosis, are the blood monocytes and the neutrophils, dendritic cells, and tissue macrophages. During an infection, monocytes circulating in the blood are recruited to the site of infection, where they differentiate into macrophages to combat the infection.
Macrophages identify microbes like bacteria through different kinds of cell surface receptors, which not only help in recognition but also aid in activating signaling pathways. It eventually induces the polymerization of actin microfilaments, thus helping the phagocyte expand its plasma membrane and engulf the microbes.
Microbes are internalized into phagosomes, followed by the fusion of lysosomes with phagosomes. Thus, the formation of phagolysosomes from the fusion kills the microbes by the hydrolytic enzymes of lysosomes activated by increasing acidity.
A phagocyte recognizes microbes by phagocytic receptors
Phagocytes mainly express pathogen-recognizing receptors (PRRs) among varieties of receptors on their surfaces. Pathogen-recognizing receptors recognize pathogen-associated molecular patterns (PAMPs) directly on microbial surfaces.
All pattern-recognizing receptors do not induce phagocytosis as the toll-like receptors(TLRs). The TLRs, being the major PRRS, do not induce the same. Some PRRs, after binding PAMPs instead of inducing phagocytosis, trigger other responses. Cell wall components like complex carbohydrates, lipopolysaccharides, peptidoglycan, and surface proteins are among the PAMPs that induce phagocytosis.
Phagocytes can recognize soluble proteins bound to surfaces of microbes, thus spurring phagocytosis, and the process is known as opsonization. These phagocytosis-enhancing soluble proteins are also known as opsonins. After their binding to microbe surfaces, opsonins are recognized by membrane opsonin receptors on phagocytes, activating phagocytosis.
Soluble proteins as opsonins
There are many varieties of soluble proteins functioning as opsonins and play diverse roles in innate immunity. The complement component C1q functions as an opsonin binds to lipopolysaccharides of bacterial cell wall components. It is recognized by the CR1 opsonin receptor, activating phagocytosis.
The collectin protein, mannose-binding lectin (MBL), is found in the blood and respiratory fluids and has opsonizing activity. Two surfactant collectin proteins, SP-A and SP-D are found in the blood and function as opsonins. These collectin proteins are recognized by the CD91 opsonin receptor and promote phagocytosis.
C-reactive protein (CRP), after recognizing phosphocholine and carbohydrates in bacteria, fungi, and parasites, becomes an opsonin bound by Fc receptors (binds with constant region of antibodies). Fc receptors are necessary for antibodies to develop their opsonizing activity. Phagocytosis is one of the most important antimicrobial effects of complement activation.
Phagocytosed microorganisms are killed by sequential processes
Microorganisms bind to phagocytes through pattern recognition receptors, opsonins, and opsonin receptors. Thus, this binding activates signaling pathways as a result, phagocytosis is initiated. Then, fusion of phagosomes with lysosomes takes place, and the resulting phagolysosomes contain anti-microbial agents, which kill the internalized microbes.
The anti-microbial agents include antimicrobial proteins and peptides like defensins and cathelicidins, hydrolytic enzymes like lysozyme and proteases, which get activated by the decreasing pH of the phagolysosomes, and certain molecules arbitrating oxidative attack.
Phagocytes attack phagocytosed microbes by releasing highly toxic reactive oxygen species (ROS) and reactive nitrogen species (RNS). This damages microbial membranes and intracellular components. This oxidative attack occurs in neutrophils, macrophages, and dendritic cells.
Generation of reactive oxygen and nitrogen species
When microorganisms attach themselves to the phagocytic receptors, the phagocytes’ unique NADPH oxidase enzyme complex gets activated. Then, the reactive oxygen species are generated, which decimate the microbes.
A respiratory burst is a metabolic process during which a cell increases its oxygen uptake manifold. This process renders the oxygen to phagocytes to produce reactive oxygen species with the help of the enzyme NADPH oxidase. NADPH oxidase converts oxygen to superoxide ions. Other reactive oxygen species are produced by additional enzymes like hydrogen peroxide and hypochlorous acid.
Reactive nitrogen species (RNS) generation depends upon the transcriptional activation of the gene for the enzyme inducible nitric oxide synthase (iNOS). When microbial PAMPs bind to various PRRs, the enzyme iNOS gets activated and oxidizes ւ-arginine to ւ-citrulline and nitric oxide (NO).
Nitric oxide combines with superoxide ion( ̇O2ˉ ) produced by NADPH oxidase to generate an additional reactive nitrogen species, peroxynitrite, and a toxic compound, S-nitrosothiols.
ROS and RNS can alternate microbes through oxidation, hydroxylation, chlorination, nitration, and S-nitrosylation. Many enzymes in their active sites contain cysteine sulfhydryl groups, which are oxidized by ROS and RNS, thus inactivating the enzymes. Activated neutrophils and macrophages can release ROS and RNS and decimate extracellular pathogens.
The enzyme NADPH oxidase produces ROS and RNS, which play a major role in eliminating microorganisms. Patients suffering from chronic granulomatous disease have lost the ability to generate ROS and RNS due to defective subunits of the enzyme NADPH oxidase. Thus, these patients show increased susceptibility to bacterial and fungal infections.
Autophagy- a process to eliminate intracellular pathogens
Some bacteria replicate in the cytosol and thus escape from phagocytosis. However, phagocytosis has an internal form known as autophagy, which helps to eliminate these bacteria. Autophagy is a process in which a membrane from the endoplasmic reticulum covers the bacteria, forming an autophagosome. The autophagosome fuses with the lysosome and destroys microbes.
How the dead cells are cleared from body
Macrophages play a major role in clearing dead cells by implementing their phagocytic receptors on cells that have died from apoptosis, cell damage, or toxic stimuli. Additionally, spleen and liver macrophages recognize, phagocytose, and degrade aging and damaged red blood cells.
The components of dead cells, also known as damage-associated molecular patterns, are recognized by pattern recognition receptors (PRRs) on phagocytes, which proceed to their clearance.
The apoptotic cells release a liquid mediator lysophosphatidic acid, which acts as a chemo-attractant. These cells express an array of molecules like phospholipids, proteins, and altered carbohydrates, which are not expressed by normal cells. Thus, this facilitates the process of phagocytosis.
Phagocytic receptors such as the phosphatidylserine receptor and scavenger receptor SR-A1 can directly recognize these damage-associated molecular patterns (DAMPs) expressed by apoptotic cells. Opsonins recognize other DAMPs, and these opsonins are recognized by opsonin receptors, thus activating phagocytosis and destroying apoptotic cells.
Macrophages destroy the aging and damaged blood cells, which before destruction and during the process of aging, accumulate the array of molecules like phospholipids, proteins, and carbohydrates in their plasma membrane. Phosphatidylserine receptors on the surface of phagocytes recognize the phosphatidylserine on the outer leaflet of the lipid bilayer of the aging cells.
Normal cell and tumor cell escaping from phagocytosis
A normal cell escapes the process of phagocytosis by releasing “do not eat me” signals. Whereas apoptotic cells enter into phagocytosis by releasing “ eat me” signals. Healthy erythrocytes express “do not eat me” signals, thus avoiding phagocytosis.
The protein CD47 is expressed on many cell types throughout our body and is recognized by the signal regulatory protein α ( SIRPα) receptor on macrophages, which transmits inhibitory signals for phagocytosis.
Tumor cells escape from the process of phagocytosis by elevated expression of CD47 protein. The protein activates SIRPα- mediated inhibition of phagocytosis by macrophages. In this case, antibodies are used to block the expression of CD47 on tumor cells, thus allowing their phagocytosis.
Conclusion
Phagocytosis is a process in which a cell develops an internal compartment by using its plasma membrane to engulf foreign particles. The professional phagocytic cells carrying out phagocytosis are the blood monocytes and the neutrophils, dendritic cells, and tissue macrophages.
Phagocytes express pathogen-recognizing receptors that recognize pathogen-associated molecular patterns (PAMPs) directly on microbial surfaces. Various soluble proteins act as opsonins and play a role in activating phagocytosis.
Phagocytes attack phagocytosed microbes by releasing highly toxic reactive oxygen species (ROS) and reactive nitrogen species (RNS), which damage microbial membranes and intracellular components.
The bacteria that escape from phagocytosis are eliminated by autophagy. It is an internal form of phagocytosis.
Macrophages through their phagocytic receptors, eliminate dead cells that have died from apoptosis, cell damage, or toxic stimuli. A normal cell escapes the process of phagocytosis by releasing “do not eat me” signals. Whereas the apoptotic cells enter into phagocytosis by releasing “ eat me” signals.
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I, Swagatika Sahu (author of this website), have done my master’s in Biotechnology. I have around twelve years of experience in writing and believe that writing is a great way to share knowledge. I hope the articles on the website will help users in enhancing their intellect in Biotechnology.