Open access peer-reviewed chapter
Abstract
The main line of defense that exists to eliminate foreign agents falls on phagocytic cells (neutrophils, dendritic cell, and macrophages), and it does so through phagocytosis, a complex cellular mechanism that occurs after the recognition and binding of the ligand by cellular receptors. Macrophages are part of a diverse lineage of innate immune cells. Once a macrophage receptor binds its ligand, a coordinated intracellular signaling cascade is activated to the clearance or otherwise of the foreign agent. Objects removed by macrophage phagocytosis include dead or dying host cells, cells opsonized with antibodies, and specific pathogens such as bacteria, fungi, parasites, and viruses. Currently, phagocytic macrophages have been shown to contribute to the killing of cancer cells, inflammatory bowel disease, atherosclerosis, Alzheimer’s disease, and schizophrenia. For this reason, phagocytic macrophages are important in critical participation for health and disease.
Keywords
- macrophages
- phagocytosis
- early phagosome
- late phagosome
- phagolysosome
1. Introduction
Macrophages are cells distributed in all body compartments under physiological conditions, presenting various forms and functions that depend on environmental stimuli. After their origin, macrophages are distributed to different tissues, taking the name of the tissue where they are maintained or circulate in the blood as monocytes until they face a foreign body, becoming macrophages [1, 2]. It is considered that the half-life of the macrophage is 70 h, and they make up 4–10% of the total leukocytes in peripheral blood, meaning that they constitute the second cell population of the immune system.
Macrophages are essential to innate immunity since they secrete more than 100 biologically active products and present diverse functions with different phenotypes, occupying dozens of extra and intracellular receptors. Owing to their versatility, macrophages actively participate in physiological and pathophysiological processes. As previously described, they have attributed three critical activities in the host: homeostasis, immune response, and phagocytosis [3].
In this chapter, we will focus on different parts of macrophage phagocytosis.
2. Background
Phagocytosis was first described by the Russian scientist Elia Metchnikoff, considered the father of cellular immunity. Between 1879 and 1882, he established a laboratory of marine biology and comparative embryology in Messina, Italy, where he observed and described this process. His description of “phagocytosis” (an evolutionarily conserved cellular process that recognizes and ingests particles larger than 0.5 microns within a vesicle derived from the plasma membrane) led to his being awarded the Nobel Prize in 1908 together with Paul Ehrlich [4].
Metchnikoff reported other macrophage functions such as resistance to infection, phagocytosis of cell debris, and tissue damage repair linking directly to immunology, gerontology, gut microbiome, and probiotics [4]. The macrophage has three distinct origins in development: tissue residents derived from the yolk sac, tissue residents from the fetal liver, and those derived from the bone marrow [5]. The macrophage is essential from the earliest stages in the development of life, performing various functions in development, growth, homeostasis, and remodeling [6].
Phagocytic cells are classified into professional phagocytes, such as neutrophils, monocytes, monocyte-derived macrophages, dendritic cells, and nonprofessional phagocytic cells, such as epithelial cells and fibroblasts [3]. Tissue macrophages are classified into subpopulations according to their location and phenotype:
Microglia macrophages in the central nervous system (CNS)
Osteoclasts in bone
Alveolar macrophages in the lung
Histiocytes in the spleen
Interstitial connective tissue and cells
Kupffer in the liver.
Monocytes are relatively inactive cells that are continuously monitoring their environment. When activated and become macrophages, they become involved in the processes of cellular homeostasis and the acute and chronic immune response. Macrophages recognize, ingest, and digest apoptotic particles, microbes, and cellular debris through phagocytosis. Its efficiency depends on the coordination of the physical characteristics of the macrophage and the particle to be phagocytosed [7]. Macrophages can phagocytose at the site where they are or migrate to the place that is required. Secondary to inflammation or tissue damage, they are attracted and activated by bacterial endotoxins, exotoxins, cytokines, and other biochemical and biological stimuli known as the pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP).
This action allows them to transform into fully activated proinflammatory or anti-inflammatory macrophages for repair and homeostasis [8].
Macrophage migration occurs due to the attraction of the molecules released by pathogens (PAMPs) and the cells themselves (DAMPs). They migrate to the site by moving through podosomes, dynamic and unstable structures that temporarily adhere by pulling and pushing due to the force of traction and protrusion.
Podosomes present filaments rich in actin and a stable multiprotein complex of seven units, the Arp2/3 complex bound to membrane plaque proteins; the podosomes accumulate F-actin, Integrin beta1, and CD44 helps them to attach, detach, and penetrate into or through tissues, the endothelial barrier through the process of chemotaxis. The chemotaxis process in the macrophage is driven by small Rho GTPase and signaling through mitogen-activated protein kinase/extracellular signal kinase (MAP/ERK) and Phosphatidylinositol-3 kinase/serine/threonine protein kinase (P13K/Akt)[7].
The initiation of migration begins with the stimulation of the chemoattractant protein 1 (MCP-1). This chemokine is produced by different tissue cells secreted under the stimulation of the cytokines tumor necrosis factor alpha (TNF alpha), IL-6, IL-1beta, and is suppressed by IL-10 [9].
Before phagocytosis, the macrophage recognizes the white particle to rule out whether it is an invader or itself. The CD47 transmembrane protein is present in all host cells and is the signal they present to avoid being phagocytosed by macrophages. Receptors carry out phagocytosis on the plasma membrane, divided into opsonic and nonopsonic receptors. Nonopsonic receptors bind directly to PAMPs and induce phagocytosis. The nonopsonic receptors are lectin-like recognition molecules such as CD169, CD33, and Dectin 1, C-type lectins (MICL, Dectin 2, Mincle, and DNGR-1), as well as scavenger receptors (Figure 1A). These receptors are considered promiscuous and have a poorly defined intracellular signaling capacity. That is why the binding of various ligands and receptors is required to ingest the particle. The opsonic receptors are those that recognize the target particle surrounded by opsonins (proteins derived from the host, such as antibodies, complement factors, fibronectin, and mannose-linked lectin), within which we find the Fcy receptors (FcyRI, FcyRII, and FcyRIII) and glycoproteins that specifically bind to the Fc region of immunoglobulin G (IgG) forming a complex that is pooled on the membrane and phagocytosed by the macrophage. This phagocytosis is also known as antibody-dependent cellular phagocytosis (ADCP) [10]. In this group, we also have complement receptors (CR) such as CR1 (CD35) CR3 (CD11/CD18 or MAC-1), scavenger receptors, and C-type lectins (Figure 1B) [3]. Scavenger receptors, such as SR-A or CD36, recognize apoptotic and microbial polyanionic ligands [11]. The toll-like receptors (TLRs) [12] are detectors of PAMPs, but they do not function as phagocytic receptors. TLRs collaborate with nonopsonic receptors to stimulate ingestion [13].
Figure 1.
Phagocytic receptors are present in the macrophage. A) Pattern recognition receptors (PRR): TLR, scavenger receptors, lectin receptors, mannose receptors, which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAM). B) Opsonic receptors: such as receptors for the crystallizable fraction of antibodies (FcR), complement receptors (CR), which recognize antibodies and C1 or C3b molecules that opsonize microorganisms and promote phagocytosis. Created with
3. Recognition of the target molecule by the macrophage
In the process of phagocytosis and the case of an infectious process, the binding of the ligand to the receptor, the dynamics of actin polymerization of the cytoskeleton of the pseudopods of the macrophage, and the mechanical stability of the fimbriae of the bacterium must be closely related and coordinated in a complex sequence of events to engulf the bacteria. Phagocytosis is initiated by the recognition of the target particle by multiple receptors, the identification of the particle’s position, and the establishment of regular physical contact until the ingestion is processed. To date, more than 100 cell surface receptors have been described that participate in macrophage activation as well as various forms of phagocytosis. The initiation of phagosome formation, and the rate at which phagosome formation proceeds on the particle, is directly related to the membrane tension that counteracts that exerted on the growing ends of the actin filaments, and owing to the Rho family GTPase-controlled actin polymerization, phagosome rigidity increases as macrophages engulf prey.
For the formation of the phagosome and the particle’s internalization, the cytoskeleton’s scaffold protein is required, which is the GTPase1 activating protein that contains the IQ motif (IQGAP1) [7].
After the receptor’s binding to the particle, the plasmatic membrane covers the microorganisms and closes at the distal end, forming a vacuole where the particles are internalized [14]. The duration of the ingestion of the particle, the formation of the phagosome, and its closure are proportional to the size of the bacterial filament, so if these times are prolonged, it has direct consequences for the survival of the pathogens inside the cells [7].
Jaumouille in 2019 points out that there are two mechanisms in the internalization of the target particle: a) activation or firing mechanism that occurs after signaling and results in the formation of membrane lifting plasmatic by actin action, and b) the zipper mechanism initiated by sequential cell surface receptors and ends with the particle surrounded by the plasmatic membrane [15]. The firing mechanism is associated with some intracellular pathogens, while the closing mechanism is associated with most pathogens. CRs trigger a distinct form of Rho family GTPase-dependent phagocytosis, characterized by a “sinking” of the particle into the cell without triggering proinflammatory mediators [16].
The recognition of the ligand by the phagocytic receptor of the macrophage is variable since there are differences according to the nature of its precursor and the signals sent by different factors, so depending on this, the response will be pro- or anti-inflammatory. Macrophages’ response and phenotype are changeable due to their high plasticity. The action of phagocytosis by macrophages is not fully known, however. For an organism to survive an infection, a prompt response is required, eliminating the microorganisms; therefore, the phagocytosis rate will depend significantly on the speed with which the macrophages identify, trap, and eliminate the intruders. To begin phagocytosis, macrophages must locate the position of the microorganism and establish physical contact for phagocytosis to occur. Macrophages use chemotaxis and apply mechanical force through lamellipodium protuberances on the leading edge driven by actin polymerization, which allows them to migrate to the site of inflammation. The chemotaxis process in macrophages is carried out by small Rho GTPases and MAPK/ERK and PI3K/Akt signaling. Different chemokines regulate these signaling pathways in human macrophages [7].
In the phagocytosis process, various stages are involved:
Detection of the particle to be phagocytosed.
Activation of the internalization process.
Formation of the specialized vacuole called phagosome.
Maturation of the phagosome to transform itself.
The detection of PAMPs occurs through pattern recognition receptors (PRRs); these PRRs are phagocytized directly or through opsonins. The lectin-like family’s nonopsonic receptors are Dectin-1, Mincle, MCL, and DC-SIGN, which bind to different PAMPs. Various target particles are surrounded by opsonins that bind to specific receptors, such as the FcyR receptor or complement receptors (CRs).
As previously mentioned, the phagocytosis process will have changes according to the ligand and the receptor; after the interaction between the receptors of the phagocytic cell with the target particle, signaling events occur to initiate phagocytosis. In the formation of the phagosome, there are changes in the lipid composition of the membrane, and significant changes occur in the remodeling of the membrane and the actin cytoskeleton leading to the formation of pseudopods that cover the microorganism due to the action of the enzymes coronin, cofilin, and gelsolin. To form pseudopods, Coronin 1 debranches F-actin, leaving it as loose fibers to be cut by cofilin and gelsolin, an action controlled by its binding to phosphoinositides. Actin filaments are knocked down or nucleated by the activity of the Arp2/3 protein complex to initiate F-actin polymerization and pseudopod formation.
The signaling pathways triggered by the best-studied phagocytic receptors are the FcRs and CRs. For FcR-mediated phagocytosis, Arp2/3 integrates into the new phagocytic cup, where its actin nucleation activity is stimulated by WASp and N-WASp [17], which are also activated by Cdc42-GTP, and PI [11, 18]. In the case of CR-mediated phagocytosis, actin polymerization is associated with RhoA. This GTPase recruits and stimulates mDia formins [19]; they also activate the Arp2/3 complex.
However, other GTPases, such as Rap, appear to play a role in CR-mediated phagocytosis, independent of RhoA [20]. Rap GTP also activates profilin, essential for actin polymerization via formins [21]. Rap GTP activates profilin, which is necessary for actin polymerization through formins [21]. Rap can also activate GTPase Rac [22].
At this point, lipids associate and dissociate from the phagosome membrane in an orderly fashion, and the GTPases Rho, Rac, and cell division cycle 42 (Cdc42), essential regulators of the actin cytoskeleton, are activated and recruited for phagosome formation. At the point of contact between the receptors and the microorganism, a depression in the membrane is formed, also called a phagocytic cup, followed by the polymerization of F-actin, triggering the pseudopod formation that surrounds the microorganism, and within minutes, they fuse at the distal end to seal and form the phagosome [14].
The action of myosin in the formation of the phagosome that is involved in its contractile activity is also known. Before the phagosome is complete, F-actin is removed from the phagocytic cup to facilitate phagosome closure by the enzyme PI 3-K. In FcyR-mediated phagocytosis, the WASP and N-WASP proteins (Wiskott-Aldrich syndrome protein) are activated to activate the Arp2/3 complex for actin polymerization at the base of the nascent phagocyte. The final part of the phagosome formation occurs when the membranes fuse in their distal portion. A moment before this step, F-actin disappears, helping to make the phagosome less rigid, an action that PI3-K is responsible for. The inhibition of this enzyme blocks the depolymerization of actin in the phagocytic cup, stopping the pseudopod extension [23].
We know that the activation of GTPases is necessary to stimulate the Arp2/3 complex during phagocytosis for actin polymerization [24]. However, PI [11, 25] P3, the PI3K product, can stimulate Rho family GTPase activation proteins (GAPs), which inactivate GTPases and prevent actin polymerization. PI3K inhibition has also increased GTPase activation in the phagocytic cup [24, 26]. PI3K activity decreases PI levels [11], P2. This phospholipid activates the Arp2/3 complex, via WASP and N-WASP [27]. Thus, the disappearance of the phagocytic cup promotes the extension of the pseudopod. As for myosins, they use their contractile activity to facilitate the formation of phagosomes [28]. In macrophages, that class II and IXb myosins were concentrated at the base of the phagocytic cups, with an increase in the phagocytic cup at its closure site. Myosin V appeared after phagosome closure [15]. In extension of the pseudopod, actin filaments move from the bottom to the top of the phagocytic cup, compressing the particle to be internalized [2]. This activity is dependent on myosin light chain kinase (MLCK). MLCK-activated myosin II is required for the contractile activity of phagocytic cups [29]. Because of this, the phagocytic cups push the fluid out of the phagosomes. Myosin X is PI3K-dependent and is essential for propagating pseudopods in phagocytosis [23]. The myosin I subclass, myosin Ic, is located at the tip of the phagocytic cup, which relates it to the generation of the force of contraction, which causes the opening of the phagocytic cup to close [23]. The myosin I subclass, myosin Ic, is located at the tip of the phagocytic cup, which relates it to the generation of the force of contraction, which causes the opening of the phagocytic cup to close [23]. Myosin IX appears in the phagocytic layers similarly to myosin II [30]. This myosin is involved in the contractile activity of phagocytic cups; it also functions as a signaling molecule for the reorganization of the actin cytoskeleton.
Myosins class IX contains a GTPase activation protein (GAP) domain that activates GTPase Rho [31] involved in actin remodeling. Myosin V appears in fully internalized phagosomes. It is involved in vesicular transport in other cells [32]; it is responsible for phagosome movement rather than phagosome formation [2].
4. Phagosome formation and binding to the lysosome
The newly formed phagosome will combine with early endosomes to form the phagolysosome [25, 33], involving membrane fusion events regulated by the Rab5 GTPase [34, 35]. Rab5 recruits early endosome antigen 1 (EEA1), a molecule that functions as a bridge between the early endosome and endocytic vesicles; it also induces the recruitment of Rab7. During phagosome maturation, Rab5 disappears, and Rab7 appears on the membrane [36]. Rab7 regulates phagosome fusion with late endosomes [37]. At this point, V-ATPase molecules accumulate on the phagosome membrane and acidify (pH 5.5–6.0) the interior of the phagosome by translocating protons (H+) into the phagosome lumen [36].
Lysosome-associated membrane proteins (LAMPs) and luminal proteases (cathepsin and hydrolases) are incorporated from fusion with late endosomes [38], culminating in the presence of hydrolytic enzymes that lead to the degradation of the microorganism, causing the breakdown of material into its essential components, and lipids, proteins, and carbohydrates are either recycled by the cell or excreted into the extracellular environment to be excreted from the body [39]. In macrophages, we find Fe2+ ions such as azurophilic granules that bind to chelators such as adenosine, myeloperoxidase (MPO) substitutes, and hydrolases and lysosomes that fuse in the phagosome and degrade microbial or apoptotic cells (Figure 2) [14].
Figure 2.
Stages of phagosome maturation. The process is divided into several stages of maturation, phagosome formation, early phagosome, late phagosome, and phagolysosome formation. The process begins when the macrophage recognizes and captures a microorganism through exposed receptors on its membrane; a phagocytic cup is produced that culminates in the formation of the phagosome; the membrane includes molecules that control membrane fusion, such as Rab5 GTPases and Rab7. By joining the late phagosome with the lysosome, degrading enzymes, such as cathepsins, proteases, lysosomals, and lipases, are integrated that will cut the microorganism. The phagolysosome will become a very acidic site due to the action of V-ATPase, which pumps protons into the vesicle to kill the microorganism. EEA1: Early endosome antigen 1; NADPH: nicotinamide adenine dinucleotide phosphate oxidase. Created with
5. The production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the function of the macrophage
In an inflammatory process, the function of the macrophage is crucial since it is responsible for limiting that inflammation. After phagocytosis, in late phagosome, the phagosome binds with the lysosome presenting an acid pH due to the action of several V-ATPases and proteases with the stimulation of the foreign agent, the macrophage produces reactive oxygen species (ROS) and nitrogen (ON) (superoxide ion and hydrogen peroxide) secondary the catalytic activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex. This reaction is preferably intracellular through electron transfer reactions within the phagolysosome, especially in the mitochondrial respiratory chain. The increase in NADPH causes oxygen consumption (respiratory burst) and the creation of toxic products such as ROS, NO*. NO is produced by inducible nitric oxide synthase (iNOS), which, in turn, stimulates further NO production.
This event is associated with various pathophysiological processes, such as the oxidation of low-density lipoproteins (LDL) that are phagocytosed by the macrophage, becoming a foamy macrophage itself, which is associated with an increased risk of atherosclerosis [10].
Despite being a mechanical-biological process studied for several years, phagocytosis still has unknown events. It is a process that is not the same for any particle that will be engulfed since there are variations according to the characteristics of the particle and the type of receptor that binds to the ligand. The examples mentioned below depend on the target particle to be phagocytosed.
6. Phagocytosis in infectious diseases
Bacteria, viruses, fungi, and parasites present various PAMPs not detected by cellular receptors called pattern recognition receptors (PRRs). There is an extensive variety of PRRs that, according to the characteristics of the receptor, will identify and bind to a specific ligand. The phagocytosis of a PAMP occurs by binding to one or various receptors and one or different PAMPs of the same pathogen in a single event. There are several examples in this regard; the polysaccharides present on the surface of some yeasts bind to the mannose receptor or the dectin-1 receptor, while the lipopolysaccharide (LPS) of gram-negative bacteria is detected by the scavenger-A receptor (SR-A). The phagocytosis of mycobacteria occurs through complement receptors (opsonization of mycobacteria by complement) or by the mannose receptor that recognizes lipoarabinomannan (LAM), a structure that is part of the wall of mycobacteria; the coating of mycobacteria by surfactant protein A (Sp-A) has also been described [40]. Fungal phagocytosis is less studied; beta-glucans of the fungal cell wall bind to Dectin-1 receptors to initiate phagocytosis [41]. While the human serum amyloid protein (SAP) is considered a Trojan horse since some fungi and bacteria have a functional SAP on their wall that allows the fungus to bind to cells and be more invasive [42].
Interestingly, it has been reported how bacteria of the genus
The importance of removing apoptotic bodies through phagocytosis is known. Many cells die every day in healthy subjects, and phagocytes must remove their apoptotic bodies. Apoptotic cells display on their surface several molecules that distinguish them from healthy cells, such as phosphatidylserine (PS), a molecule restricted to the inner layer of the plasma membrane in healthy cells, which appears on the surface during the apoptosis process. In a sterile inflammation event produced by cells such as neutrophils that have been recruited to the site of inflammation and undergo cell death by apoptosis, they are phagocyted to decrease or eliminate tissue-damaging proinflammatory factors and ROS. This process called spherocytosis is the part of the interaction of a complex network involving binding molecules, molecules that signal the cell through PS that helps tissue homeostasis [45]. It is a complex mechanism by which various interactions are related as ligand-receptor and signals. Cells undergoing apoptosis release multiple molecules such as ATP, lysophosphatidylcholine, fractalkine, and sphingosine 1-phosphate. These molecules act as chemotactic factors that recruit phagocytes to the site of cell death. Multiple phagocytic receptors bind PS. Direct binding to PS is mediated by receptors such as TIM1, brain-specific angiogenesis inhibitor 1 (BAI1), and stabilin-2 [30]. In other cases, the molecules can bind to PS and to surface receptors forming a bridge; an example of this is MFG-E8 that links PS to αVβ3 integrins, which are effective phagocytic receptors.
Another example is Gas6 and protein S molecules that are between PS and phagocytic receptors, such as TAMs (Tyro3, Axl, Mer) [46]. Derivatives of PS metabolism may also contribute to the recognition of apoptotic bodies. PS appears to undergo oxidation, and some phagocytic receptors, such as CD36 and CD68, bind modified lipids, including oxidized PS [30].
7. Macrophage response in phagocytosis
The macrophage presents high metabolic plasticity, which is associated with the polarization of the macrophage and the molecules and factors they produce, so their response will be unique in each case. The macrophage response can be controlled by the target particle inducing specific signaling pathways directed by receptors that recognize the target particle and by overlapping signaling pathways.
An example is phagocytosis secondary to antibodies recognition that is controlled by protein kinase C (KPC) without stimulating phosphatidylinositol 3-kinase or extracellular signal regulated kinases (ERK). However, antibody phagocytosis stimulates these last two molecules through cytokines and depending on these multiple factors, we have the macrophages 0 (M0), which are naïve macrophages, M1 characterized by proinflammatory and accompanied by IL-6, IL-12, and TNF alpha, M2, which are anti-inflammatory and produce IL-10, TGF-beta, and Arginase; Mreg are regulatory macrophages with anti-inflammatory characteristics and IL-10 producers. Other recently reported macrophages, such as M-mox and M4, are mentioned, but less is known about them. The M2 group is classified into M2a, M2b, M2c, and M2d.
This classification, carried out practically for a better understanding, is based on the expressed transcription factors and the signaling pathways used by macrophages. However, these macrophages display high plasticity and change their status depending on the medium and environmental signals. Despite the plasticity of macrophages, three responses are recognized, two of which are well characterized. The description of the macrophage’s immune response is diverse and changing since it depends on the characteristics of the target particle, especially if it is a pathogen, the receptors responsible for binding to that particle, and whether or not it is opsonized and the capacity of the macrophage to remove the foreign agent.
One of many examples is the binding of polysaccharide from fungi to mannose or Dectin-1 receptors, the binding of lipopolysaccharide from a gram negative bacterium to TLRs, or the binding of bacteria to SR-A or framework. Each of these events will stimulate transcription factors and stimulus-dependent signaling pathways. Even with this diversity, we can state in general that there is an immune response that is characterized by the production of various molecules such as lipases, nucleases, proteases, glycosidases, and phosphatases responsible for degrading the target particle, the expression of NADPH oxidase (Nox2), and oxide synthase 2 (Nos2) responsible to produce reactive oxygen and nitrogen species. In infections, the macrophage activates proteins that sequester iron (Fe) and Mn, essential elements for microorganisms.
8. Conclusions
In this chapter, we show the complexity of phagocytosis from the clue particle recognition going through physicochemical characteristics between macrophage and the target particle to the development of the phagolysosome. Phagocytosis is not as simple as it sounds, even though we know the types of immune responses promoted by the macrophage; recent research shows that the variability may be wider. That is why more research is required to broaden the knowledge of phagocytosis, which will help improve patient’s clinical conditions.
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