For the ecological classification, see Macrophage (ecology).
Macrophages (abbreviated as Mφ, MΦ or MP) (Greek: large eaters, from Greek μακρός (makrós) = large, φαγεῖν (phagein) = to eat) are a type of white blood cell of the immune system that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells on its surface in a process called phagocytosis.
Besides phagocytosis, they play a critical role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes.
In humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections.
Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages.
This difference is reflected in their metabolism; M1 macrophages have the unique ability to metabolize arginine to the "killer" molecule nitric oxide, whereas rodent M2 macrophages have the unique ability to metabolize arginine to the "repair" molecule ornithine.
However, this dichotomy has been recently questioned as further complexity has been discovered.
Human macrophages are about 21 micrometres (0.00083 in) in diameter and are produced by the differentiation of monocytes in tissues.
They can be identified using flow cytometry or immunohistochemical staining by their specific expression of proteins such as CD14, CD40, CD11b, CD64, F4/80 (mice)/EMR1 (human), lysozyme M, MAC-1/MAC-3 and CD68.
Macrophages were first discovered by Élie Metchnikoff, a Russian zoologist, in 1884.
Main article: Mononuclear phagocyte system
A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of foreign particles is likely to occur.
These cells together as a group are known as the mononuclear phagocyte system and were previously known as the reticuloendothelial system.
Each type of macrophage, determined by its location, has a specific name:
|Cell Name||Anatomical Location|
|Adipose tissue macrophages||Adipose tissue (fat)|
|Monocytes||Bone marrow / blood|
|Sinus histiocytes||Lymph nodes|
|Alveolar macrophages (dust cells)||Pulmonary alveoli|
|Tissue macrophages (histiocytes) leading to giant cells||Connective tissue|
|Microglia||Central nervous system|
|Intraglomerular mesangial cells||Kidney|
|Red pulp macrophages (sinusoidal lining cells)||Red pulp of spleen|
|Peritoneal macrophages||Peritoneal cavity|
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.
Macrophages can be classified on basis of the fundamental function and activation.
Macrophages that reside in adult healthy tissues either derive from circulating monocytes or are established before birth and then maintained during adult life independently of monocytes.
By contrast, most of the macrophages that accumulate at diseased sites typically derive from circulating monocytes.
Monocytes are attracted to a damaged site by chemical substances through chemotaxis, 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 several months.
Main article: Phagocytosis
Macrophages are professional phagocytes and are highly specialized in removal of dying or dead cells and cellular debris.
This role is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophils, which are ingested by macrophages if they come of age (see CD31 for a description of this process).
The neutrophils are at first attracted to a site, where they perform their function and die, before they are phagocytized by the macrophages.
When at the site, the first wave of neutrophils, after the process of aging and after the first 48 hours, stimulate the appearance of the macrophages whereby these macrophages will then ingest the aged neutrophils.
The removal of dying cells 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.
Within the phagolysosome, enzymes and toxic peroxides digest the pathogen.
However, some bacteria, such as Mycobacterium tuberculosis, have become resistant to these methods of digestion.
Typhoidal Salmonellae induce their own phagocytosis by host macrophages in vivo, and inhibit digestion by lysosomal action, thereby using macrophages for their own replication and causing macrophage apoptosis.
Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds.
Role in adaptive immunity
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.
Role in wound healing
Macrophages are essential for wound healing.
They replace polymorphonuclear neutrophils as the predominant cells in the wound by day two after injury.
Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls.
Numbers of monocytes in the wound peak one to one and a half days after the injury occurs.
Once they are in the wound site, monocytes mature into macrophages.
The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue.
The macrophage's main role is to phagocytize bacteria and damaged tissue, and they also debride damaged tissue by releasing proteases.
Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wound days.
These factors attract cells involved in the proliferation stage of healing to the area.
Macrophages may also restrain the contraction phase.
Macrophages are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis and they also stimulate cells that re-epithelialize the wound, create granulation tissue, and lay down a new extracellular matrix.
By secreting these factors, macrophages contribute to pushing the wound healing process into the next phase.
Role in limb regeneration
Scientists have elucidated that as well as eating up material debris, macrophages are involved in the typical limb regeneration in the salamander.
They found that removing the macrophages from a salamander resulted in failure of limb regeneration and a scarring response.
Role in iron homeostasis
Main article: Human iron metabolism
As described above, macrophages play a key role in removing dying or dead cells and cellular debris.
Erythrocytes have a lifespan on average of 120 days and so are constantly being destroyed by macrophages in the spleen and liver.
In cases where systemic iron levels are raised, or where inflammation is present, raised levels of hepcidin act on macrophage ferroportin channels, leading to iron remaining within the macrophages.
Role in pigment retainment
Melanophages are a subset of tissue-resident macrophages able to absorb pigment, either native to the organism or exogenous (such as tattoos), from extracellular space.
In contrast to dendritic juncional melanocytes, which synthesize melanosomes and contain various stages of their development, the melanophages only accumulate phagocytosed melanin in lysosome-like phagosomes.
This occurs repeatedly as the pigment from dead dermal macrophages is phagocytosed by their successors, preserving the tattoo in the same place.
Role in tissue homeostasis
Every tissue harbors its own specialized population of resident macrophages, which entertain reciprocal interconnections with the stroma and functional tissue.
These resident macrophages are sessile (non-migratory), provide essential growth factors to support the physiological function of the tissue (e.g. macrophage-neuronal crosstalk in the guts), and can actively protect the tissue from inflammatory damage.
Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system.
For example, they participate in the formation of granulomas, 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.
As a host for intracellular pathogens
In their role as a phagocytic immune cell macrophages are responsible for engulfing pathogens to destroy them.
Some pathogens subvert this process and instead live inside the macrophage.
This provides an environment in which the pathogen is hidden from the immune system and allows it to replicate.
In order to minimize the possibility of becoming the host of an intracellular bacteria, macrophages have evolved defense mechanisms such as induction of nitric oxide and reactive oxygen intermediates, which are toxic to microbes.
Macrophages have also evolved the ability to restrict the microbe's nutrient supply and induce autophagy.
Once engulfed by a macrophage, the causative agent of tuberculosis, Mycobacterium tuberculosis, avoids cellular defenses and uses the cell to replicate.
Upon phagocytosis by a macrophage, the Leishmania parasite finds itself in a phagocytic vacuole.
Under normal circumstances, this phagocytic vacuole would develop into a lysosome and its contents would be digested.
Leishmania alter this process and avoid being destroyed; instead, they make a home inside the vacuole.
Infection of macrophages in joints is associated with local inflammation during and after the acute phase of Chikungunya (caused by CHIKV or Chikungunya virus).
Adenovirus (most common cause of pink eye) can remain latent in a host macrophage, with continued viral shedding 6–18 months after initial infection.
Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis.
Focal recruitment of macrophages occurs after the onset of acute myocardial infarction.
These macrophages function to remove debris, apoptotic cells and to prepare for tissue regeneration.
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.
Macrophages are better able to resist infection by HIV-1 than CD4+ T cells, although susceptibility to HIV infection differs among macrophage subtypes.
Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells.
NF-κB then enters the nucleus of a tumor cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation.
Moreover, macrophages serve as a source for many pro-angiogenic factors including vascular endothelial factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), Macrophage colony-stimulating factor (M-CSF/CSF1) and IL-1 and IL-6 contributing further to the tumor growth.
Macrophages have been shown to infiltrate a number of tumors.
Their number correlates with poor prognosis in certain cancers including cancers of breast, cervix, bladder, brain and prostate.
Tumor-associated macrophages (TAMs) are thought to acquire an M2 phenotype, contributing to tumor growth and progression.
Research in various study models suggests that macrophages can sometimes acquire anti-tumor functions.
For example, macrophages may have cytotoxic activity to kill tumor cells directly; also the co-operation of T-cells and macrophages is important to suppress tumors.
This co-operation involves not only the direct contact of T-cell and macrophage, with antigen presentation, but also includes the secretion of adequate combinations of cytokines, which enhance T-cell antitumor activity.
Recent study findings suggest that by forcing IFN-α expression in tumor-infiltrating macrophages, it is possible to blunt their innate protumoral activity and reprogram the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity.
Additionally, subcapsular sinus macrophages in tumor-draining lymph nodes can suppress cancer progression by containing the spread of tumor-derived materials.
Macrophages can influence treatment outcomes both positively and negatively.
Macrophages can be protective in different ways: they can remove dead tumor cells (in a process called phagocytosis) following treatments that kill these cells; they can serve as drug depots for some anticancer drugs; they can also be activated by some therapies to promote antitumor immunity.
Macrophages can also be deleterious in several ways: for example they can suppress various chemotherapies, radiotherapies and immunotherapies.
Because macrophages can regulate tumor progression, therapeutic strategies to reduce the number of these cells, or to manipulate their phenotypes, are currently being tested in cancer patients.
However, macrophages are also involved in antibody mediated cytotoxicity (ADCC)and this mechanism has been proposed to be important for certain cancer immunotherapy antibodies.
It has been observed that increased number of pro-inflammatory macrophages within obese adipose tissue contributes to obesity complications including insulin resistance and diabetes type 2.
Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.
In an obese individual some adipocytes burst and undergo necrotic death, which causes the residential M2 macrophages to switch to M1 phenotype.
This is one of the causes of a low-grade systemic chronic inflammatory state associated with obesity.
Though very similar in structure to tissue macrophages, intestinal macrophages have evolved specific characteristics and functions given their natural environment, which is in the digestive tract.
Macrophages and intestinal macrophages have high plasticity causing their phenotype to be altered by their environments.
Like macrophages, intestinal macrophages are differentiated monocytes, though intestinal macrophages have to coexist with the microbiome in the intestines.
This is a challenge considering the bacteria found in the gut are not recognized as "self" and could be potential targets for phagocytosis by the macrophage.
To prevent the destruction of the gut bacteria, intestinal macrophages have developed key differences compared to other macrophages.
Primarily, intestinal macrophages do not induce inflammatory responses.
Whereas tissue macrophages release various inflammatory cytokines, such as IL-1, IL-6 and TNF-α, intestinal macrophages do not produce or secrete inflammatory cytokines.
This change is directly caused by the intestinal macrophages environment.
Surrounding intestinal epithelial cells release TGF-β, which induces the change from proinflammatory macrophage to noninflammatory macrophage.
Even though the inflammatory response is downregulated in intestinal macrophages, phagocytosis is still carried out.
There is no drop off in phagocytosis efficiency as intestinal macrophages are able to effectively phagocytize the bacteria,S.
typhimurium and E. , but intestinal macrophages still do not release cytokines, even after phagocytosis. coli
Also, intestinal macrophages do not express lipoplysaccharide (LPS), IgA, or IgG receptors.
The lack of LPS receptors is important for the gut as the intestinal macrophages do not detect the microbe-associated molecular patterns (MAMPS/PAMPS) of the intestinal microbiome.
Nor do they express IL-2 and IL-3 growth factor receptors.
Role in disease
In a healthy gut, intestinal macrophages limit the inflammatory response in the gut, but in a disease-state, intestinal macrophage numbers and diversity are altered.
This leads to inflammation of the gut and disease symptoms of IBD.
Intestinal macrophages are critical in maintaining gut homeostasis.
The presence of inflammation or pathogen alters this homeostasis, and concurrently alters the intestinal macrophages.
There has yet to be a determined mechanism for the alteration of the intestinal macrophages by recruitment of new monocytes or changes in the already present intestinal macrophages.
Credits to the contents of this page go to the authors of the corresponding Wikipedia page: en.wikipedia.org/wiki/Macrophage.