Corpus: Macrophage

Macrophages are large, motile, mononuclear cells that are part of the cellular immune system. They develop from the peripheral monocytes circulating in the blood, which have a half-life of approx. 72 hours. Monocytes can migrate into the tissue and remain there for several weeks to months as tissue macrophages.

Macrophages develop from the monocytes formed in the bone marrow. These cells are flushed out into the blood vessels and circulate through the body in the bloodstream. During an infection, they are attracted to the site of infection by chemotaxis and differentiate into macrophages under the influence of cytokines and antigens in the tissue. They can be activated by IL-1 or interferon-gamma, for example.

Macrophages are about 21 µm in size and, like granulocytes, are amoeboid motile. They can be differentiated from other blood cells based on the expression of specific surface proteins using flow cytometry or immunohistochemistry. These include, for example, CD14, CD11b, CD68, EMR1, lysozyme M or MAC-1/MAC-3.

A distinction is made between site-independent, mobile (also: motile) macrophages, which migrate from the blood as required, and stationary, sessile tissue macrophages, which make up the majority of the macrophage population. The tissue macrophages are bound to a specific tissue and sometimes differ greatly from each other in their morphology. The following forms are differentiated:

• in connective tissue: histiocyte
• in the brain: microglial cell
• in the lungs: alveolar macrophage
• in the liver: Kupffer's stellate cell
• in the placenta: Hofbauer cell
• in the bone: osteoclast
• in skin: Langerhans cell

Macrophages react differently to contact with different stimuli, such as cytokines, PAMPs and DAMPs. Therefore, two phenotypes are distinguished in the literature.

M1 phenotype[Bearbeiten]

Endotoxins such as lipopolysaccharides (LPS) or proinflammatory cytokines (e.g. TNF-α, interferon-γ etc.) trigger the formation of a strongly proinflammatory macrophage phenotype, the so-called M1 phenotype. This is characterised by the production of the enzyme iNOS (inducible NO synthase) and the consecutive formation of NO radicals, which have a strong cytotoxic effect on surrounding cells. Furthermore, this phenotype also releases pro-inflammatory cytokines to initiate an immune response, e.g. as a reaction to pathogens, but also after tissue injuries to "clean up" the resulting cell debris.

M2 phenotype[Bearbeiten]

Anti-inflammatory cytokines such as IL-4 or tissue debris, such as myelin after a peripheral nerve injury, lead to the induction of an anti-inflammatory M2 phenotype with a high phagocytosis capacity. In the context of tissue regeneration, this phenotype is often referred to as "pre-regenerative", as it stimulates the differentiation of stem cells and also releases growth factors and anti-inflammatory cytokines that lead to the proliferation of the corresponding cells in the tissue. The M2 phenotype is also common in tumours: Almost all solid tissue tumours are characterised by a high expression of M2 marker proteins, such as arginase 1 (Arg-1). It is assumed that the anti-inflammatory M2 macrophages contribute to immunosuppression in the tumour microenvironment and thus to immune evasion and tumour growth.

As part of the mononuclear-phagocytic system (MPS), macrophages have a variety of functions in the context of pathogen defence:

• Central role in the initiation and regulation of defence reactions (inflammation)
• phagocytosis
• Destruction of tumour cells
• Removal of cell detritus
• (obligatory) antigen presentation
• Wound healing

Phagocytosis[Bearbeiten]

Macrophages recognise pathogens via so-called pattern recognition receptors, such as the TLR. Their most important task is the phagocytosis of microorganisms and other foreign bodies as part of the non-specific defence. The cytoplasm of macrophages contains a large number of lysosomes, which contain lytic enzymes that can be used to kill phagocytised pathogens. This process leads to the so-called "activation" of the macrophage and subsequently to the secretion of cytokines, which control the inflammatory reaction.

Antigen presentation[Bearbeiten]

Macrophages also have an important function as antigen-presenting cells (APC). Macrophages process phagocytised pathogens into peptide fragments, which they present on the cell surface with the help of MHC-II molecules. The antigen-MHC-II complexes are recognised by T helper cells, which then trigger the production of specific antibodies.

Production of cytokines[Bearbeiten]

Contact with pathogens (such as lipopolysaccharides) leads to the activation of macrophages via a pattern recognition receptor, which results in the secretion of numerous cytokines and pro-inflammatory factors such as IL-1β, IL-2, IL-6 and TNF-α. The presence of zinc can further increase this effect. Therefore, if a patient suffering from a bacterial infection is receiving parenteral nutrition, the intravenous addition of zinc ions can trigger a fever spike. In order to prevent an uncontrolled immune reaction, anti-inflammatory cytokines such as IL-10 are also expressed by macrophages after some time.

Muscle regeneration[Bearbeiten]

Non-phagocytic macrophages play an important role in the repair of damaged muscle fibres. It is assumed that macrophages influence the healing process through the secretion of as yet unidentified proteins that control the proliferation and differentiation of muscle cells.

Peripheral nerve regeneration[Bearbeiten]

Macrophages are active in peripheral nerve regeneration. In the first phase after a nerve injury, it is mainly M1 macrophages that are active, which stimulate the immune system to break down the degenerating nerve stump. In the further course, M2 macrophages dominate, phagocytising myelin and dead cells and contributing to the differentiation of Schwann cells by releasing cytokines.

Virus replication[Bearbeiten]

In the spleen, CD169-positive macrophages make a decisive contribution to the production of sufficient virus particles in viral infections to induce an immune response. The viruses are virtually "incubated" in them. This stimulates the differentiation and proliferation of the lymphocytes. The CD169-positive macrophages are completely surrounded by other macrophages, which intercept and destroy any viruses that escape to the outside.