Immunology

Macrophage – Definition, Structure, Mechanism, Functions

Macrophage Structure of Macrophages Development of macrophages Mechanism of Macrophage A macrophage is an immune cell that eliminates pathogens by the following...

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Macrophage - Definition, Structure, Mechanism, Functions
Macrophage - Definition, Structure, Mechanism, Functions

Macrophage

  • The macrophage is a type of white blood cell that aids in the elimination of foreign substances by ingesting them and activating an immunological response.
  • Macrophages are components of the reticuloendothelial system (or mononuclear phagocyte system) and are found in nearly all bodily tissues.
  • In certain circumstances, macrophages are immobile within tissues, such as in lymph nodes and the intestines. In other instances, they may roam the crevices between connective tissues.
  • As a collective, they can consume other cells, pathogenic agents, and several other minute particles, such as specific colours and colloids.
  • By consuming and processing foreign particles, macrophages serve a crucial role in allowing lymphocytes, which determine the specificity of the immune response, to recognise them.
  • Monocytes in the bone marrow differentiate into macrophages. The granulocyte-macrophage colony-stimulating factor stimulates the development of precursor cells into monocytes.
  • After leaving the bone marrow, they circulate in the circulation. Hours later, the monocytes penetrate the tissues, where they transform into macrophages.
  • The primary cells implicated in chronic inflammation are macrophages, which often become more prominent at the site of injury only after days or weeks.
  • Several of their effects contribute to the progression of tissue injury and the resulting functional impairment. Consequently, they are commonly regarded as a biological marker of persistent inflammation.
  • In different organs, specialised macrophages are known by different names; for example, those in the liver are known as Kupffer cells, whilst those in the skin are known as Langerhans cells.
  • The mononuclear phagocyte system is comprised of these cells, which originate from promonocytes in the bone marrow and differentiate into monocytes in the circulation before settling in the tissues as mature macrophages.
  • They are present throughout connective tissue and around the basement membrane of small blood vessels, and are especially concentrated in the lung (alveolar macrophages), liver (Kupffer cells), and lining of the spleen sinusoids and lymph node medullary sinuses, where they are strategically positioned to filter out foreign material.
  • Other examples are mesangial cells in the glomerulus of the kidney, microglia in the brain, and osteoclasts in bone.
  • In contrast to neutrophils, macrophages are longlived cells with a significant amount of roughsurfaced endoplasmic reticulum and mitochondria. Whereas neutrophils provide the primary defence against pyogenic (pusforming) bacteria, macrophages are most effective against bacteria, viruses, and protozoa that are capable of living within the host’s cells.
Structure of Macrophages
Structure of Macrophages

Structure of Macrophages

  • The shape of macrophages is dependent upon the various states of cell activity. The diameter of the cells ranges between 10 and 30 µm.
  • Basophilic vacuoles and granules can be found in the cytoplasm of macrophages. The nucleus is ovoid and has a diameter of around 6-12 m.
  • Under a phase-contrast microscope, peritoneal macrophages have diffuse, light-gray cytoplasm with rod-shaped mitochondria.
  • The cytoplasm’s perimeter is composed of coarsely granular material and is devoid of endoplasmic reticulum and ribosomes.
  • Three distinct types of vesicles are evident in the cytoplasm as pinocytic vesicles containing organelles of varying sizes and diner granular material.
  • Attached to the exterior section of the nuclear membrane that is continuous with the endoplasmic reticulum are ribosomes.
  • The majority of the dense granules in the cytoplasm are secondary lysosomes, which originate from endocytic vacuoles.
  • In the case of inflammatory macrophages, thin cytoplasmic extensions closely interweave with neighbouring epithelioid cells are detected.
  • As a result of the merging of pre-existing macrophages, some data may even imply the presence of large granuloma cells.
Origin and Development of Macrophages
Origin and Development of Macrophages

Development of macrophages

  • Macrophages have several origins. Tissue-resident macrophages can either differentiate from circulating monocytes that develop from hematopoietic stem cells in the bone marrow or originate during embryonic development in the foetal liver, the yolk sac, or an embryonic region near the dorsal aorta and are therefore maintained independently of monocytes throughout adulthood.
  • The development of persistent tissue-specific macrophages, including macrophages of the bone (osteoclasts), central nervous system (microglia), connective tissue (histiocytes), and liver (Kupffer cells), as well as macrophages of the alveoli (dust cells), intestine, spleen, and peritoneum, is facilitated by the ability of monocytes to migrate into tissues either in the steady state or in response to inflammation.
  • Microglial and Kupffer cells are capable of self-renewal in the presence of interleukin 34 (IL-34), which is produced in these tissues and binds to the same receptor as macrophage colony-stimulating factor (M-CSF).
  • Macrophages exhibit many morphologies and phenotypes as a result of their distribution and function in numerous tissues and organs.
Development of macrophages
Development of macrophages

Mechanism of Macrophage

A macrophage is an immune cell that eliminates pathogens by the following set of steps:

Antigen Recognition

  • Macrophages identify antigens such as bacteria and other organisms through their toll-like receptors system (TLRs).
  • These receptors recognise the characteristics of pathogens, such as lipopolysaccharides, nucleic acids, or extracellular proteins such as flagellin from bacterial flagella, and then bind to them precisely.
  • The binding of an antigen to TLRs generates an alarm signal that activates and mobilises other immune cells to combat the antigen.

Microbial Killing

  • Macrophages mediate innate immune responses largely against bacteria and not viruses. Macrophage cannot eliminate the viral infection on its own.
  • T cells generate an antiviral mechanism that destroys the virus. Therefore, the macrophages then remove the dead virus particles.
  • Therefore, macrophages utilise any of the two modes of pathogen destruction to eliminate bacterial cells (oxygen-dependent or oxygen-independent).
  • After recognising a pathogen, macrophages become activated and exhibit a greater propensity to phagocytose it. Additionally, it emits inflammatory factors.

Oxygen-independent Killing

  • It is the process through which vesicles containing bacterial invaders are absorbed into the macrophage (Phagosome).
  • Eventually, the lysosomes (vesicles containing hydrolytic enzymes) will fuse with the phagosome enclosing the pathogens, resulting in the target organism’s destruction. It employs a set of enzymes to eliminate bacterial cells:
    • Before destroying the cell membrane, electrically charged proteins are initially produced.
    • Second, lysozymes are used to degrade the bacterial cell wall.
    • Then, lactoferrins are utilised to extract vital iron from bacteria.
    • Last but not least, lysosomal proteolytic and hydrolytic enzymes degrade the proteins of dead bacteria.
    • Ultimately, the bacterial cell transforms into microscopic particles that are expelled from the cell by fusing the leftover body with the cell membrane.

Oxygen-dependent Killing

By superoxide dismutase

  • As soon as the macrophage consumes the germs, it begins to consume more oxygen, resulting in a respiratory burst. In response, macrophages generate reactive oxygen species (ROS) or superoxides, which are oxygen-rich antimicrobial substances.
  • Superoxide dismutase catalyses the conversion of superoxide to hydrogen peroxide and singlet oxygen. Additionally, superoxide combines with hydrogen peroxide to generate hydroxyl radicals, which aid in the destruction of the invading microorganism.

By nitric oxide synthase

  • After macrophage activation, the synthesis of nitric oxide synthase increases to enhance the generation of peroxynitrite radicals by the reaction of nitric oxide with hydrogen peroxide.

By myeloperoxidase

  • This enzyme complex was discovered in neutrophil granules. When neutrophil granules come into touch with a phagosome, they form a phagolysosome and begin releasing myeloperoxidase.
  • Utilizing hydrogen peroxide and chlorine, this enzyme produces a highly toxic antimicrobial compound (hypochlorite).
  • Within the cellular compartments, the radicals produced by these enzyme systems can be damaging to both the pathogen and the cell itself.
  • Using ROS and RNS molecules to kill invading bacteria is referred to as oxygen-dependent intracellular death.

Present Antigen to T cell

  • In addition to releasing oxidative radicals, macrophages also release cytotoxic substances such as TNF-alpha, IL-1, 8, and 12 in order to induce an inflammatory response.
  • A macrophage (antigen-presenting cell) will finally manufacture MHC class II molecules (present antigens to TH cells). Therefore, macrophages and T lymphocytes work together to combat the foreign body.
Differentiation of Macrophages from Hematopoietic Stem Cells
Differentiation of Macrophages from Hematopoietic Stem Cells

Types of Macrophages

The macrophage reaches the target cell’s tissues, where it assists foreign body invasion or phagocytosis and removes dead cells. Therefore, macrophages comprise the mononuclear phagocyte system, a collection of phagocytic cells. Previously, macrophages were referred to as the reticuloendothelial system.

Types of Macrophages Based on Location

Depending on its location, many types of macrophages can be distinguished.

  1. Alveolar macrophage: It is present in the alveoli of the lungs and consumes tiny particles, dead cells, and germs. In addition, it stimulates the immune system in the event that respiratory pathogens are encountered.
  2. Kupffer cells: The tissues of the liver contain Kupffer cells, which trigger immunological responses and drive hepatic tissue remodelling.
  3. Microglia: Microglia are positioned in the central nervous system, where they remove old or dead neurons and regulate brain immunity.
  4. Splenic macrophages: Macrophages of the spleen are also known as marginal zone, metallophilic, and red pulp macrophages. The marginal zone of the spleen contains red and white pulp, which disposes of non-functional and aged erythrocytes.
  5. Testicular macrophages: It is found in Leydig cells, which are testicular macrophages. It establishes an immune-privileged milieu in the testis by converting 25-hydroxycholesterol, an oxysterol, to testosterone.
  6. Cardiac resident macrophages: Cardiac resident macrophages engage in electrical conduction by communicating with cardiac myocytes via gap junctions.
Tissue-specific Macrophages
Tissue-specific Macrophages

Based on Function & Activation

In accordance with their function and activation, macrophages are classified into three subtypes:

  • Classically activated M1 macrophages: These macrophages are M1 macrophages that have been classically activated.
  • Alternatively activated M2 macrophages: These macrophages are also known as alternatively activated macrophages, and they are responsible for wound healing.
  • Mregs: Mregs are macrophages that regulate the activity of other immune cells.

Macrophages exhibit considerable heterogeneity due to the following factors:

  • Several distinct locations.
  • Their dissimilar morphologies.
  • A pattern they use to recognise infections.
  • Their production of inflammatory cytokines (such as IL-1, IL-6, and tumour necrosis factor-alpha).

Therefore, macrophage heterogeneity is inherited from the precursors of monocytes, from which they differentiated and specialised to perform diverse roles.

Classically activated M1 macrophages

  • Through innate and adaptive immune responses, M1 macrophages primarily serve in Th1 cell recruitment, pathogen resistance, and tumour management.
  • Pathogens, LPS, granulocyte macrophage-colony stimulating factor (GM-CSF), tumour necrosis factor alpha (TNF-α), and the T helper 1 (Th1) cell cytokine interferon gamma (IFN-γ) can typically stimulate the polarisation of macrophages into M1 cells.
  • Numerous pathways, including IRF/STAT, LPS/TLR4, and NF-κB/PI-3 kinase, are implicated in driving macrophages to M1 polarisation.
  • Antigen presentation activity and synthesis of pro-inflammatory cytokines, including as interleukin 1 (IL-1), IL-6, and TNF-α, as well as nitric oxide (NO) and reactive oxygen species, are prominent features of M1 macrophages (ROS).
  • In addition, they exhibit overexpression of IL-12 and IL-23 and downregulation of IL-10. Stimulating M1 macrophages induces significant levels of IL-1b, TNF-α, IL-12, IL-18, and IL-23 production.
  • In addition, it has been demonstrated that the M1 macrophage phenotype expresses high levels of major histocompatibility complex class II (MHC II), CD68, CD80, and CD86, as well as the Th1 cell-attracting chemokines CXCL9 and CXCL12.
Characteristics of M1 Macrophages
Characteristics of M1 Macrophages

Alternatively activated M2 macrophages

  • M2 macrophages can be activated alternately by parasite or fungal infection, immune complexes, apoptotic cells, macrophage colony-stimulating factor (M-CSF), IL-13, TGF-b, and T helper 2 (Th2) cytokine IL-4, as well as by IL-33 and IL-25 via Th2 cells. STAT6, IRF4, PPARδ, and PPARγ are all involved in the signalling that pushes macrophages into the M2 state.
  • In contrast to the conventionally activated subtype, the alternatively activated subtype has the inverse expression profile, with downregulation of IL-12 and IL-23 and overexpression of IL-10 and IL-1RA.
  • Moreover, M2 macrophages produce low levels of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α. In addition to pathogen clearance, anti-inflammatory response, and metabolism, M2 macrophages are involved in wound healing, tissue remodelling, immunoregulation, tumour growth, and malignancies.
  • Expressions of CD206, CD163, CD209, FIZZ1 and Ym1/2 are indicative of the M2 phenotype. In general, this subtype demonstrates a high level of expression of receptors essential for the phagocytosis and scavenging of mannose and galactose, as well as a high level of ornithine and polyamine synthesis via the arginase pathway.
  • This macrophage type expresses the chemokines CCL1, CCL17, CCL18, CCL22, and CCL24.
Characteristics of M2 Macrophages
Characteristics of M2 Macrophages

Subtypes of M2 macrophages

Four M2 subtypes, M2a, M2b, M2c, and M2d, have been identified based on the activation of M2 macrophages individually. On the basis of their cell surface markers, secreted cytokines, and biological roles, these subtypes differ from one another. Nonetheless, all subtypes of M2 macrophages have IL-10 expression.

Macrophage Subtypes in Atherosclerosis
Macrophage Subtypes in Atherosclerosis
  • M2a macrophages: Activation of M2a macrophages by IL-4 or IL-13. In turn, IL-4 induces the expression of the mannose receptor (CD206). It has been established that further elevation of IL-10, TGF-b, CCL17, CCL18, and CCL22 promotes cell proliferation, tissue healing, and endocytosis.
  • M2b macrophages: Immune complexes, Toll-like receptor (TLR) ligands, and IL-1b activate M2b macrophages. This subtype releases the pro- and anti-inflammatory cytokines TNF-α, IL-1b, IL-6, and IL-10 during activation. The purpose of M2b macrophages is to regulate the immune response and inflammation.
  • M2c macrophages: Activation of M2c macrophages by glucocorticoids, IL-10, and TGF-b (and inactivated macrophages). This subtype is distinguished by high levels of anti-inflammatory IL-10, pro-fibrotic TGF-b, CCL16, CCL18, and the Mer receptor tyrosine kinase (MerTK), which promotes phagocytosis of apoptotic cells.
  • M2d macrophages: Activation of M2d macrophages by TLR antagonists, IL-6, and adenosines. The expression of IL-10 and vascular endothelial growth factor (VEGF) is induced by adenosines, which in turn induces angiogenesis and tumour progression.
M2 Macrophage Subtypes
M2 Macrophage Subtypes

Functions of Macrophages

The following are some of macrophages’ functions:

  • As part of homeostasis, macrophages are responsible for removing dead cells and cellular waste. Phagocytosis is one of the primary innate immune system mechanisms.
  • In addition to presenting antigens to other immune cells, macrophages also initiate an immunological response. These cells also release a range of chemokines other potent chemicals that regulate the activation of adaptive immune cells.
  • Macrophages participate in muscle repair, growth, and regeneration following inflammation at various places.
  • M2 macrophages are also known as wound-healing macrophages due to their ability to control inflammation and promote tissue repair and regeneration.
  • As scavengers, macrophages continuously remove dead erythrocytes from the circulation. The process stores iron released during the process in the form of ferritin, hence contributing to iron homeostasis.
Macrophage Polarization by T-helper Cells
Macrophage Polarization by T-helper Cells

References

  • Kumar, V. (2019). Macrophages: The Potent Immunoregulatory Innate Immune Cells. In  (Ed.), Macrophage Activation – Biology and Disease. IntechOpen. https://doi.org/10.5772/intechopen.88013
  • Shibata, Y., Abiko, Y., Takiguchi, H. (1991). Macrophage Membrane: Structure and Function. In: Harris, J.R. (eds) Megakaryocytes, Platelets, Macrophages, and Eosinophils. Blood Cell Biochemistry, vol 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9531-8_8
  • Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016 Mar 15;44(3):450-462. doi: 10.1016/j.immuni.2016.02.015. PMID: 26982353; PMCID: PMC4794754.
  • Gordon, Siamon ; Martinez-Pomares, Luisa Berlin/Heidelberg: Springer Berlin Heidelberg Pflügers Archiv, 2017, Vol.469 (3-4), p.365-374
  • Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013 Apr 25;496(7446):445-55. doi: 10.1038/nature12034. PMID: 23619691; PMCID: PMC3725458.
  • Verschoor CP, Puchta A, Bowdish DM. The macrophage. Methods Mol Biol. 2012;844:139-56. doi: 10.1007/978-1-61779-527-5_10. PMID: 22262440.
  • Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014 Jul 17;41(1):21-35. doi: 10.1016/j.immuni.2014.06.013. PMID: 25035951; PMCID: PMC4470379.
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  • https://biologyreader.com/macrophages.html
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