Macrophage
Overview
 
Macrophages are cell
Cell
-Science and technology:*Cell , the functional basic unit of life*Cell , a term used in an electronic circuit design schematics*Cell , a three-dimensional element, part of a higher-dimensional object*Cell , a scientific journal...

s produced by the differentiation of monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s in tissues. Human macrophages are about 21 um in diameter. Monocytes and macrophages are phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...

s. Macrophages function in both non-specific defense (innate immunity) as well as help initiate specific defense mechanisms (adaptive immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s, either as stationary or as mobile cells.
Encyclopedia
Macrophages are cell
Cell
-Science and technology:*Cell , the functional basic unit of life*Cell , a term used in an electronic circuit design schematics*Cell , a three-dimensional element, part of a higher-dimensional object*Cell , a scientific journal...

s produced by the differentiation of monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s in tissues. Human macrophages are about 21 um in diameter. Monocytes and macrophages are phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...

s. Macrophages function in both non-specific defense (innate immunity) as well as help initiate specific defense mechanisms (adaptive immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s, either as stationary or as mobile cells. They also stimulate lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

s and other immune cells to respond to pathogens. They are specialized phagocytic cells that attack foreign substances, infectious microbes and cancer cells through destruction and ingestion.
Macrophages can be identified by specific expression of a number of proteins including CD14
CD14
Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form...

, CD11b, F4/80
F4/80
F4/80 is a transmembrane protein present on the cell-surface of mouse Macrophages, which are derived from the myeloid lineage. It has an approximate mass of 125kDa, and is associated with mature macrophages. The human analog is EMR1....

 (mice)/EMR1
EMR1
EGF-like module-containing mucin-like hormone receptor-like 1 is a protein that in humans is encoded by the EMR1 gene.-Further reading:...

 (human), lysozyme
Lysozyme
Lysozyme, also known as muramidase or N-acetylmuramide glycanhydrolase, are glycoside hydrolases, enzymes that damage bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between...

 M, MAC-1
Mac-1
MAC-1 may refer to:* Macrophage-1 antigen* Integrin alpha M...

/MAC-3 and CD68
CD68
CD68 is a glycoprotein which binds to low density lipoprotein.It is expressed on monocytes/macrophages.The mouse equivalent is called "macrosialin".-Use in pathology:...

 by flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...

 or immunohistochemical staining. They move by action of amoeboid movement
Amoeboid movement
Amoeboid movement is a crawling-like type of movement accomplished by protrusion of cytoplasm of the cell involving the formation of pseudopodia. The cytoplasm slides and forms a pseudopodium in front to move the cell forward. This type of movement has been linked to changes in action potential;...

.

Life cycle

When a leukocyte enters damaged tissue through the endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 of a blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

 (a process known as the leukocyte extravasation
Leukocyte extravasation
Leukocyte extravasation is the movement of leukocytes out of the circulatory system, towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes...

), it undergoes a series of changes to become a macrophage. Monocytes are attracted to a damaged site by chemical substances through chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

, triggered by a range of stimuli including damaged cells, pathogens and cytokines released by macrophages already at the site. At some sites such as the testis, macrophages have been shown to populate the organ through proliferation.
Unlike short-lived neutrophils, macrophages survive longer in the body up to a maximum of several months.

Function

Phagocytosis

One important role of the macrophage is the removal of necrotic
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 cellular debris in the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

s. Removing dead cell material is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophil granulocyte
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...

s, which are ingested by macrophages if they come of age (see CD-31 for a description of this process.)

The removal of necrotic tissue is, to a greater extent, handled by fixed macrophages, which will stay at strategic locations such as the lungs, liver, neural tissue, bone, spleen and connective tissue, ingesting foreign materials such as pathogens and recruiting additional macrophages if needed.

When a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome, which then fuses with a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

. Within the phagolysosome, enzymes and toxic peroxides digest the pathogen. However, some bacteria, such as Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...

, have become resistant to these methods of digestion. Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds.

Role in adaptive immunity

Macrophages are versatile cells that play many roles. As scavengers, they rid the body of worn-out cells and other debris. Along with dendritic cells, they are foremost among the cells that "present" antigen, a crucial role in initiating an immune response. As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation; they produce a wide array of powerful chemical substances (monokine
Monokine
A monokine is a type of cytokine produced primarily by monocytes and macrophages.Examples include interleukin 1 and tumor necrosis factor-alpha.Other monokines include alpha and beta interferon, and colony stimulating factors.-Functions:...

s) including enzymes, complement proteins, and regulatory factors such as interleukin-1. At the same time, they carry receptors for lymphokine
Lymphokine
Lymphokines are a subset of cytokines that are produced by a type of immune cell known as a lymphocyte. They are protein mediators typically produced by T cells to direct the immune system response by signalling between its cells...

s that allow them to be "activated" into single-minded pursuit of microbes and tumour cells.

After digesting a pathogen, a macrophage will present the antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

 (a molecule, most often a protein found on the surface of the pathogen, used by the immune system for identification) of the pathogen to the corresponding helper T cell. The presentation is done by integrating it into the cell membrane and displaying it attached to an MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...

 class II molecule, indicating to other white blood cells that the macrophage is not a pathogen, despite having antigens on its surface.

Eventually, the antigen presentation results in the production of antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 that attach to the antigens of pathogens, making them easier for macrophages to adhere to with their cell membrane and phagocytose. In some cases, pathogens are very resistant to adhesion by the macrophages.

The antigen presentation on the surface of infected macrophages (in the context of MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...

 class II) in a lymph node stimulates TH1
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...

 (type 1 helper T cells) to proliferate (mainly due to IL-12
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...

 secretion from the macrophage). When a B-cell in the lymph node recognizes the same unprocessed surface antigen on the bacterium with its surface bound antibody, the antigen is endocytosed and processed. The processed antigen is then presented in MHCII on the surface of the B-cell. T cells that express the T cell receptor which recognizes the antigen-MHCII complex (with co-stimulatory factors- CD40 and CD40L) cause the B-cell to produce antibodies that help opsonisation of the antigen so that the bacteria can be better cleared by phagocytes.

Macrophages provide yet another line of defense against tumor cells and somatic cells infected with fungus
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...

 or parasites. Once a T cell has recognized its particular antigen on the surface of an aberrant cell, the T cell becomes an activated effector cell, producing chemical mediators known as lymphokine
Lymphokine
Lymphokines are a subset of cytokines that are produced by a type of immune cell known as a lymphocyte. They are protein mediators typically produced by T cells to direct the immune system response by signalling between its cells...

s that stimulate macrophages into a more aggressive form.

Currently, it is a major opinion that there are several activated forms of macrophages. In spite of a spectrum of ways to activate macrophages, historically they have been classfied into two main groups designated M1 and M2. M1 macrophages are immune effector cells that are aggressive against microbes and can engulf and digest affected cells much more readily, and they also produce many lymphokines. As more ways to activate macrophages become apparent, the M2 designation is becoming a catch-all to describe other types, including those that function in wound healing and tissue repair, and those that turn off immune system activation by producing anti-inflammatory cytokines like IL-10.

Role in muscle regeneration

The first step to understanding the importance of macrophages in muscle repair, growth, and regeneration is that there are two “waves” of macrophages with the onset of damageable muscle use – subpopulations that do and do not directly have an influence on repairing muscle. The initial wave is a phagocytic population that comes along during periods of increased muscle use that are sufficient to cause muscle membrane lysis and membrane inflammation, which can enter and degrade the contents of injured muscle fibers. These early-invading, phagocytic macrophages reach their highest concentration about 24 hours following the onset of some form of muscle cell injury or reloading. Their concentration rapidly declines after 48 hours. The second group is the non-phagocytic types that are distributed near regenerative fibers. These peak between two and four days and remain elevated for several days during the hopeful muscle rebuilding. The first subpopulation has no direct benefit to repairing muscle, while the second non-phagocytic group does.

It is thought that macrophages release soluble substances that influence the proliferation, differentiation, growth, repair, and regeneration of muscle, but at this time the factor that is produced to mediate these effects is unknown. It is known that macrophages' involvement in promoting tissue repair is not muscle specific; they accumulate in numerous tissues during the healing process phase following injury.

A study conducted in 2006 showcased macrophage influences on muscle repair of soleus muscle on mice.

The first procedural step was to make sure macrophages are present in the muscle after onset of muscle injury, and then decrease their presence to see what effects were had on the muscle. By using anti-F4/80 to bind to macrophages and render them useless, it was seen that when the second wave of macrophages were depleted, there were many more lesions in the muscle cell membrane between the second and fourth day – showing muscle damage when repairing is supposed to occur. After testing for membrane lesions in both the total amount of muscle fibers present, it was noticed that most of the damage occurred in muscle cells that did not have the second subpopulation of macrophages present. Macrophages depletion prevents muscle membrane repair.

When examining muscle regeneration, a significant reduction was found in the amount of myonuclei. Depletion of macrophages was found to cause, between the second and fourth day of repair, much less muscle regeneration compared to muscle with macrophage population. Macrophages promote muscle regeneration between the second and fourth day.

To determine the influence of macrophages in muscle growth, muscle cross-sectional area in macrophage-depleted muscle area was measured against two muscle sets: muscle that was injured and had macrophage presence and muscle that was not injured and had macrophage presence. The macrophage-depleted muscle showed less growth after four days, and injured muscle with macrophages nearly grew back to the level of uninjured muscle. Macrophage depletion reduces muscle growth during a growth period.

The study attempted to examine the appearances of Pax7
PAX7
Paired box protein Pax-7 is a protein that in humans is encoded by the PAX7 gene.- Function :Pax-7 plays a role in neural crest development and gastrulation, and it is an important factor in the expression of neural crest markers such as Slug, Sox9, Sox10 and HNK-1....

 and MyoD
MyoD
MyoD is a protein with a key role in regulating muscle differentiation. MyoD belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 .MyoD is one...

, but data was not consistent with previous findings.

Tissue macrophages

A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of dust is likely to occur. Each type of macrophage, determined by its location, has a specific name:
| Intraglomerular mesangial cells > | Giant cell
Giant cell
A giant cell is a mass formed by the union of several distinct cells . It can arise in response to an infection or foreign body.Types include:* foreign-body giant cell* Langhans giant cell* Touton giant cells...

s >
Name of cell Location
>-
| Dust cell
Dust cell
An alveolar macrophage is a type of macrophage found in the pulmonary alveolus, near the pneumocytes, but separated from the wall....

s/Alveolar macrophages
pulmonary alveolus
Pulmonary alveolus
An alveolus is an anatomical structure that has the form of a hollow cavity. Found in the lung parenchyma, the pulmonary alveoli are the dead ends of the respiratory tree, which outcrop from either alveolar sacs or alveolar ducts, which are both sites of gas exchange with the blood as well...

 of lungs
>-
| Histiocytes 
connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...


>-
| Kupffer cell
Kupffer cell
Kupffer cells, also known as Browicz-Kupffer cells and stellate macrophages, are specialized macrophages located in the liver lining the walls of the sinusoids that form part of the reticuloendothelial system .-History:The cells were first observed by Karl Wilhelm von Kupffer in 1876...

s
liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...


>-
| Microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...

 
>-
| Epithelioid
Epithelioid
An epithelioid cell is a cell that resembles epithelial cells in that it directly contacts its neighboring cells via cell surface molecules or junctions. Unlike epithelial cells, however, epithelioid cells make contacts over their entire surface, rather than at restricted portions. The term...

 cells
>-
| Osteoclasts 
bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...


>-
| Sinusoidal lining cells
spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

Connective Tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...



Investigations concerning Kupffer cells are hampered because in humans Kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies. From rats and mice they are difficult to isolate and after purification only approximately 5 million cells can be obtained from one mouse.

Macrophages can express paracrine functions within organs that are specific to the function of that organ. In the testis for example, macrophages have been shown to be able to interact with Leydig cells by secreting 25-hydroxycholesterol, an oxysterol that can be converted to testosterone by neighbouring Leydig cells. Also, testicular macrophages may participate in creating an immune privileged environment in the testis, and in mediating infertility during inflammation of the testis.

Disease

Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system. For example, they participate in the formation of granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...

s, inflammatory lesions that may be caused by a large number of diseases. Some disorders, mostly rare, of ineffective phagocytosis and macrophage function have been described, for example.

Tuberculosis

Once engulfed by a macrophage the causititve agent of tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...

  avoids cellular defenses and uses the cell to replicate.

Heart disease

Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

.

HIV infection

Macrophages also play a role in Human Immunodeficiency Virus (HIV) infection. Like T cells, macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. HIV can enter the macrophage through binding of gp120 to CD4 and second membrane receptor, CCR5 (a chemokine receptor). Both circulating monocytes and macrophages serve as a reservoir for the virus.

Cancer

Macrophages are believed to help cancer cells proliferate as well. They are attracted to oxygen-starved (hypoxic
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

) tumour cells and promote chronic inflammation. Inflammatory compounds such as Tumor necrosis factor
Tumor necrosis factor
Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...

 (TNF) released by the macrophage activates the gene switch nuclear factor-kappa B. NF-κB then enters the nucleus of a tumour cell and turns on production of proteins that stop apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

and promote cell proliferation and inflammation.

External links

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