Macrophage

Metschnikov I, 1880

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

Macrophages develop in the bone marrow from multipotent progenitor cells. They circulate as CD14-positive monocytes in the bloodstream and invade lesional tissue under cytokine control.

The focal accumulation of macrophages is termed a granuloma.

In lesional tissue, CD14-positive peripheral human blood monocytes differentiate under the influence of the cytokines M-CSF and GM-CSF, to CD68-positive "mature" macrophages. Such differentiated macrophages lose the CD14 antigen characteristic of monocytes during 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).

The following 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 cellular components. For example, from microorganisms, from overaged degenerated cells, from tumor cells, tissue debris (e.g. from inflammatory reactions) or from invaded foreign bodies.

Depending on the nature of a pathogen and the associated type of stimulation, macrophages change their cell shape. Some reduce their cell format, they are then called epithelioid cells or epithelioid cells (epitheloid=epithelial-like). Other macrophages can transform (by fusion or nuclear divisions) into multinucleated giant cells (foreign body giant cells, Langhans or Touton type giant cells) and are then able to enclose and phagocytose larger foreign bodies. Others exhibit a foamy (foam cell xanthoma cells) or stained cytoplasm (melanophages, siderophages) due to phagocytosed 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 Enzyme, Catalytic Polypeptide), which can be used to insert mutations into retroviruses that inhibit their replication.

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)

Macrophages recognize and phagocytose as antigen-presenting cells (APCs), in different ways, exogenous materials or also pathologically altered, endogenous proteins, glycoproteins, lipids. After these (if possible) have been broken down and processed intracellularly, 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, recruiting further inflammatory cells from the bloodstream. These in turn now signal back to the macrophages to destroy the previously phagocytosed material. In contrast to dendritic cells (DCs), which also present antigen, activated macrophages have a limited ability to activate naive T cells (i.e., those that have not yet come into contact with an antigen) (see antigen presentation below).

Differentiation to M1- / M2-macrophages: Further differentiation pathways for macrophages are on the one hand the "classical" activation pathway leading to M1-macrophages. On the other hand, the "alternative" activation pathway leading to 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 costimulation(CD80, CD86). M1 macrophages develop from naive (non-activated) macrophages during 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 tumor necrosis factor-alpha. Furthermore, M1 macrophages 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 preferential immunosuppressive effect. M2 macrophages exhibit a distinct phagocytosis capability. 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): Tumor-associated (M2) macrophages, also called TAM, form in a tumor milieu in the presence of IL-4 and IL-10 and M-CSF, macrophage colony-stimulating factor. The interleukins IL-4 and IL-10 play a key role in differentiation. Tumor-associated macrophages are phenotypically classified as M2 macrophages. They are characterized by a marked expression of CD163 and CD206 but are not able to destroy tumor cells. Likewise, they are not capable of presenting tumor antigens to induce an effective cell toxic immune response.

GM1 macrophages: GM-CSF (granulocyte-monocyte colony-stimulating factor ), a T-cell cytokine, induces a non-activated macrophage type from progenitor cells, also known as GMCSF macrophage. In the presence of proinflammatory signals, CD16+ GM-CSF macrophages are activated to form GM1 macrophages. GM1 macrophages exhibit little capacity for 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.

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