Macrophage

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 17.07.2021

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Synonym(s)

GM1 Macrophage; M1 Macrophage; M2 Macrophage; Macrophage (engl.); Macrophages; Tumor-associated macrophages

History
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Metschnikov I, 1880

Definition
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Macrophages (from Greek macros "big" and phagein "eat") are an essential part of the innate immune system. After the epithelial barrier, they represent the first "line of defence" against invading pathogens and phylogenetically probably represent the oldest cells of the innate immune defence. Thus, macrophage-like cells can already be detected in the fruit fly Drosophila.

Macrophages develop in the bone marrow from multipotent precursor cells. They circulate as CD14-positive monocytes in the bloodstream and invade, cytokine-controlled, into lesioned tissue.

In lesional tissue, CD14-positive peripheral human blood monocytes differentiate into CD68-positive "mature" macrophages under the influence of the cytokines M-CSF and GM-CSF. Such differentiated macrophages lose the CD14 antigen characteristic of monocytes in this activation pathway (Gordon S et al. 2005). In contrast, all different macrophage types express the marker CD68. CD68 is a component of intracellular lysosomal membrane proteins (Becker S et al.1987; Brown BN et al. 2009).

Thefollowing common functions characterize all macrophage populations: phagocytosis, antigen presentation and cytotoxicity. Furthermore, macrophages influence the extracellular matrix (ECM) and secrete arachidonic acid derivatives, growth and complement factors and various enzymes. Most macrophages are capable of phagocytosis of pathogenically altered cell components. For example, microorganisms, overaged degenerated cells, tumour cells, tissue debris (e.g. from inflammatory reactions) or foreign bodies that have entered the cell.

Depending on the type of pathogen and the type of stimulation associated with it, macrophages change their cell shape. Some reduce their cell format, they are then called epitheloid cells or epitheloid cells (epitheloid=epithelium-like). Other macrophages can transform (by fusion or nuclear division) into multinucleated giant cells (foreign body giant cells, Langhans cells) and are then able to enclose and phagocytise larger foreign bodies. Others show a foamy (foam cells) or stained cytoplasm (melanophages, siderophages) due to phagocyted material (e.g. lipids).

Macrophages (but also many other cells and even epithelial cells) contain RNA and DNA-editing enzymes, such as AID (Activation-Induced Cytidine Deaminase) and APOBEC (Apolipoprotein B mRNA-Editing Enzymes, Catalytic Polypeptides), which can be used to insert mutations into retroviruses that inhibit their replication.

Classification
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In the versch. organs and tissues, special morphological and functional forms of differentiation have developed which are called

  • resident macrophages
  • the short-lived exudate macrophages

compared to the short-lived exudate macrophages. Exudate macrophages develop under inflammatory conditions from circulating blood monocytes. They differentiate in the tissue to become important effector cells of inflammation, disintegrate there, or migrate lymphogenically to the regional lymph nodes.

Some of the resident macrophages differentiated early in embryogenesis. These include the microglial cells of the brain, the Langerhans cells of the skin and the Kupffer cells of the liver.

The resident macrophages include:

  • Macrophages of loose connective tissue(histiocytes).
  • Macrophages in granulomas (epithelioid cells, Langhans giant cells, Touton giant cells)
  • Macrophages of the spleen, lymph nodes and bone marrow (interstitial macrophages)
  • Macrophages of the serous membranes (e.g. of the peritoneum, pleura)
  • Macrophages of the liver (v. Kupffer's stellate cells)
  • Macrophages in the walls of the pulmonary alveoli (alveolar macrophages)
  • Macrophages of the bone (osteoclasts)
  • Macrophages of the cartilage tissue (chondroclasts)
  • Macrophages of the placenta (Hofbauer cells)
  • Plasmacytoid dendritic cells
  • Interdigitating cells of the lymphatic tissue
  • Special macrophages of the lymphatic tissue in the germinal centers or pulp of the spleen and lymph nodes
  • Macrophages of the vitreous humor of the eye (hyalocytes).

Purely descriptively, macrophages may also be named after the phagocytized material:

  • Lipid-storing macrophages (lipophages or foam cells).
  • Mucus-storing macrophages (muciphages)
  • Iron- or hemosiderin-storing macrophages (siderophages)
  • Melanin-storing macrophages(melanophages)
  • Foreign body-storing macrophages (foreign body giant cells, Touton giant cells)

General information
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Macrophages recognize and phagocytize as antigen-presenting cells (APCs), in different ways foreign materials or pathologically modified endogenous proteins, glycoproteins, lipids. After these have been (if possible) intracellularly comminuted and processed, they can be presented to other immune cells together with MHC-I or MHC-II complexes. These immune cells activated in this way release a different cytokine pattern(TH1 cytokines, Th2 cytokines) depending on the antigen, whereby further inflammatory cells are recruited from the blood stream. These in turn now return a signal to the macrophages to destroy the previously phagocyted material. In contrast to dendritic cells (DCs), which also present antigens, activated macrophages have only a limited ability to activate naive T cells (i.e. cells that have not yet come into contact with an antigen) (see below on antigen presentation).

Differentiation of M1 / M2 macrophages

Further differentiation pathways for macrophages are on the one hand the "classical" activation pathway leading to the M1-macrophages. On the other hand the "alternative" activation pathway leading to the M2-macrophages.

M1-macrophages

M1 macrophages are effector cells of the immune system and express receptors for opsonization(CD16) and/or antigen presentation (HLA-DR) or co-stimulation(CD80, CD86). M1 macrophages develop from naive (non-activated) macrophages in bacterial infections by activation with interferon gamma and LPS. LPS is a glycolipid derived from the cell wall of bacteria. M1-macrophages secrete the interleukins IL-1, IL-12, IL-23 and the tumor necrosis factor- alpha. M1 macrophages also produce nitrogen (NO) and oxygen radicals. Cytotoxic M1 macrophages can also destroy tumor cells (Allavena P et al. 2008).

M2-macrophages

M2-macrophages have a preferred immunosuppressive effect. M2-macrophages show a distinct phagocytosis ability. However, they are only capable of presenting antigens to a limited extent. M2-macrophages promote wound healing and angiogenesis. They secrete large amounts of Interleukin 10 (IL-10) and to a lesser extent Interleukin 12 (IL-12). M1 macrophages synthesize the chemokines CCL2 and CCL18, and express scavenger(CD163) and mannose receptors(CD206 - Goerdt S et al 1999).

Tumor-associated (M2) macrophages (TAM)

Tumour-associated (M2) macrophages, also known as TAM, are formed in a tumour environment in the presence of IL-4 and IL-10 and M-CSF, the macrophage colony stimulating factor. The interleukins IL-4 and IL-10 play a key role in differentiation. Tumor-associated macrophages are phenotypically assigned to M2-macrophages. They are characterized by a prominent expression of CD163 and CD206 but are not capable of destroying tumor cells. They are also not capable of presenting tumor antigens to induce an effective cytotoxic immune response.

GM1 macrophages

GM-CSF (granulocyte-monocyte-colony stimulating factor), a T-cell cytokine, induces a non-activated macrophage type from precursor cells, also known as GMCSF macrophage. In the presence of proinflammatory signals, the CD16+ GM-CSF macrophages are activated to GM1 macrophages. GM1-macrophages have only a low ability to phagocytosis. GM1 macrophages are not classified as M2 macrophages because they lack the surface proteins characteristic of M2 macrophages such as scavenger(CD163) and mannose(CD206) receptors. Little is known about their exact functions.

Literature
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Last updated on: 17.07.2021