Macrophages, sometimes called macrophagocytes, are cells produced by the differentiation
of monocytes in tissues.
Macrophages were discovered by Ilya Mechnikov, a Russian bacteriologist, in 1884.
Human macrophages are about 21 micrometres in diameter.
Monocytes and macrophages are phagocytes.
Macrophages function in both non-specific defense as well as help initiate specific
defense mechanisms of vertebrate animals.
Macrophages have the unique ability to metabolize one amino acid, arginine, to either a "killer"
molecule or a "repair" molecule.
Macrophages predominantly expressing the killer phenotype are called M1 macrophages, whereas
those involved in tissue repair are called M2 macrophages.
The role of macrophages is to phagocytose, or engulf and then digest, cellular debris
and pathogens, either as stationary or as mobile cells.
They also stimulate lymphocytes 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.
They are present in all living tissues, and have a function in regeneration.
Macrophages can be identified by specific expression of a number of proteins including
CD14, CD40, CD11b, CD64, F4EMR1, lysozyme M, MAC-1/MAC-3 and CD68 by flow cytometry
or immunohistochemical staining.
They move by action of amoeboid movement.
Life cycle When a monocyte enters damaged tissue through
the endothelium of a blood vessel, a process known as the leukocyte extravasation, it undergoes
a series of changes to become a macrophage.
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 a maximum
of several months.
Function
Phagocytosis
Macrophages 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 neutrophil granulocytes, which are ingested by macrophages if they come of age.
The neutrophils are at first attracted to a site, where they proliferate, 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.
When a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome, which
then fuses with a lysosome.
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 too induce their own phagocytosis by host macrophages in vivo,
and inhibit digestion by lysosomal action, thereby use macrophages to replicate and cause
macrophage apoptosis.
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 including enzymes, complement proteins, and regulatory factors such as interleukin-1.
At the same time, they carry receptors for lymphokines 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 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 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 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 a lymph node stimulates
TH1 to proliferate.
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 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 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 lymphokines
that stimulate macrophages into a more aggressive form.
Some believe that there are several activated forms of macrophages.
In spite of a spectrum of ways to activate macrophages, there are two main groups designated
M1 and M2.
M1 macrophages, as mentioned earlier, M1 "killer" macrophages are activated by LPS and IFN-gamma,
and secrete high levels of IL-12 and low levels of IL-10.
In contrast, the M2 "repair" designation broadly refers to macrophages that function in constructive
processes like wound healing and tissue repair, and those that turn off damaging immune system
activation by producing anti-inflammatory cytokines like IL-10.
M2 is the phenotype of resident tissue macrophages, and can be further elevated by IL-4.
M2 macrophages produce high levels of IL-10, TGF-beta and low levels of IL-12.
Tumor-associated macrophages are mainly of the M2 phenotype, and seem to actively promote
tumor growth.
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 two
days 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-wounding 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 reepithelialize
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
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.
Macrophages will also engulf macromolecules, and so play a key role in the pharmacokinetics
of parenteral irons.
The iron that is released from the haemoglobin is either stored internally in ferritin or
is released into the circulation via ferroportin.
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.
Tissue macrophages
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:
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 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.
Diseases with this type of behaviour include tuberculosis and leishmaniasis.
Tuberculosis Once engulfed by a macrophage, the causative
agent of tuberculosis, Mycobacterium tuberculosis, avoids cellular defenses and uses the cell
to replicate.
Leishmaniasis 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.
Chikungunya Infection of macrophages in joints is associated
with local inflammation during and after the acute phase of Chikungunya.
Others Adenovirus can remain latent in host macrophage,
with continued viral shedding 6–18 months after initial infection.
Brucella spp.
can remain latent in macrophage via inhibition of phagosome–lysosome fusion; causes brucellosis.
Heart disease Macrophages are the predominant cells involved
in creating the progressive plaque lesions of atherosclerosis.
HIV infection Macrophages also play a role in Human Immunodeficiency
Virus 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.
Both circulating monocytes and macrophages serve as a reservoir for the virus.
Cancer Macrophages contribute to tumor growth and
progression.
Attracted to oxygen-starved and necrotic tumor cells they promote chronic inflammation.
Inflammatory compounds such as Tumor necrosis factor-alpha released by the macrophages activate
the gene switch nuclear factor-kappa B. 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, tumor necrosis factor-alpha, granulocyte macrophage colony-stimulating
factor 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 and brain.
Tumor-associated macrophages are thought to acquire an M2 phenotype, contributing to tumor
growth and progression.
Recent study findings suggest that by forcing IFN-α expression in tumor-infiltrating macrophages,
it is possible to blunt their innate protumoral activity and reprogramme the tumor microenvironment
toward more effective dendritic cell activation and immune effector cell cytotoxicity.
Obesity Increased number of pro-inflammatory macrophages
within obese adipose tissue contributes to obesity complications including insulin resistance
and diabetes type 2.
Media
See also Dendritic cell
Histiocyte References
External links HIV and the Macrophage A book on the role
of macrophages in AIDS pathogenesis The role of macrophages in HIV pathogenesis
Macrophages News Macrophages News provided by insciences organisation
www.macrophages.com The Macrophage Community Website