Microglia
Encyclopedia
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
(CNS). Microglia constitute 20% of the total glial cell population within the brain. Microglia (and astrocytes) are distributed in large non-overlapping regions throughout the brain and spinal cord.
Microglia are constantly scavenging the CNS for damaged neurons, plaques, and infectious agents. The brain and spinal cord are considered "immune privileged" organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier
, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood-brain barrier, microglial cells must react quickly to decrease inflammation
and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (few antibodies are small enough to cross the blood brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. They achieve this sensitivity in part by having unique potassium channels that respond to even small changes in extracellular potassium.
from hematopoietic stem cells, the progenitors
of all blood cells. During hematopoiesis, some of these stem cells differentiate into monocyte
s and travel from the bone marrow to the brain, where they settle and further differentiate into microglia.
Monocytes can also differentiate into myeloid dendritic cells and macrophages in the peripheral systems. Like macrophages in the rest of the body, microglia use phagocytic and cytotoxic mechanisms to destroy foreign materials. Microglia and macrophages both contribute to the immune response by acting as antigen presenting cells, as well as promoting inflammation and homeostatic mechanisms within the body by secreting cytokines and other signaling molecules.
In their downregulated form, microglia lack the MHC class I
/MHC class II
proteins, IFN-γ cytokines, CD45 antigens
, and many other surface receptors required to act in the antigen-presenting, phagocytic, and cytotoxic roles that hallmark normal macrophages. Microglia also differ from macrophages in that they are much more tightly regulated spatially and temporally in order to maintain a precise immune response.
Another difference between microglia and other cells that differentiate from myeloid progenitor cells is the turnover rate. Macrophages and dendritic cells are constantly being used up and replaced by myeloid progenitor cells which differentiate into the needed type. Due to the blood brain barrier, it would be fairly difficult for the body to constantly replace microglia. Therefore, instead of constantly being replaced with myeloid progenitor cells, the microglia maintain their status quo while in their quiescent state, and then, when they are activated, they rapidly proliferate in order to keep their numbers up. Bone chimera studies have shown, however, that in cases of extreme infection
the blood-brain barrier
will weaken, and microglia will be replaced with haematogenous, cart-marrow derived cells, namely myeloid progenitor cells and macrophages. Once the infection has decreased the disconnect between peripheral and central systems is reestablished and only microglia are present for the recovery and regrowth period.
. Franz Nissl and F. Robertson first described microglial cells during their histology
experiments. The cell staining techniques in the 1880s showed that microglia are related to macrophages. The activation of microglia and formation of ramified microglial clusters was first noted by Victor Babeş
while studying a rabies
case in 1897. Babeş noted the cells were found in a variety of viral
brain infections but did not know what the clusters of microglia he saw were. Pío del Río Hortega, a student of Santiago Ramón y Cajal
, first called the cells "microglia" around 1920. He went on to characterize microglial response to brain lesions in 1927 and note the "fountains of microglia" present in the corpus callosum and other perinatal white matter
areas in 1932. After many years of research Rio-Hortega became generally considered as the "Father of Microglia." For a long period of time little improvement was made in our knowledge of microglia. Then, in 1988, Hickey and Kimura showed that perivascular microglial cells are bone-marrow derived, and express high levels of MHC class II
proteins used for antigen presentation. This confirmed Pio Del Rio-Hortega's postulate that microglial cells functioned similarly to macrophages by performing phagocytosis and antigen presentation
.
areas in the corpus callosum
known as the "Fountains of Microglia." This shape allows the microglial free movement throughout the neural tissue, which allows it to fulfill its role as a scavenger cell. Ameboid microglia are able to phagocytose debris, but do not fulfill the same antigen-presenting and inflammatory roles as activated microglia. Ameboid microglia are especially prevalent during the development and rewiring of the brain, when there are large amounts of extracellular debris and apoptotic cells to remove.
. Unlike activated or ameboid microglia, ramified microglia are unable to phagocytose cells and display little or no immunomolecules. This includes the MHC class I/II proteins normally used by macrophages and dendritic cells to present antigens to t-cells, and as a result ramified microglia function extremely poorly as antigen presenters. The purpose of this state is to maintain a constant level of available microglia to detect and fight infection, while maintaining an immunologically silent environment.
factors, lipopolysaccharide, and changes in extracellular potassium (indicative of ruptured cells). Once activated the cells undergo several key morphological changes including the thickening and retraction of branches, uptake of MHC class I/II proteins, expression of immunomolecules, secretion of cytotoxic factors, secretion of recruitment molecules, and secretion of pro-inflammatory signaling molecules (resulting in a pro-inflammation signal cascade). Activated non-phagocytic microglia generally appear as "bushy," "rods," or small ameboids depending on how far along the ramified to full phagocytic transformation continuum they are. In addition, the microglia also undergo rapid proliferation in order to increase their numbers for the upcoming battle. From a strictly morphological perspective, the variation in microglial form along the continuum is associated with changing morphological complexity and can be quantitated using the methods of fractal analysis, which have proven sensitive to even subtle, visually undetectable changes associated with different morphologies in different pathological states.
mediating signaling of activated non-phagocytic microglia, they are also able to phagocytose foreign materials and display the resulting immunomolecules for T-cell activation. Phagocytic microglia travel to the site of the injury, engulf the offending material, and secrete pro-inflammatory factors to promote more cells to proliferate and do the same. Activated phagocytic microglia also interact with astrocytes and neural cells to fight off the infection as quickly as possible with minimal damage to the healthy brain cells.
. They perform normal microglial functions, but unlike normal microglia they are replaced by bone marrow
derived precursor cells on a regular basis and express MHC class II
antigens regardless of the outside environment. Perivascular microglia also react strongly to macrophage differentiation antigens. These microglia have been shown to be essential to repair of vascular
walls, as shown by Ritter's experiments and observations on ischemic retinopathy. Perivascular microglia promote endothelial cell proliferation allowing new vessels to be formed and damaged vessels to be repaired. During repair and development, myeloid
recruitment and differentiation into microglial cells is highly accelerated to accomplish these tasks.
wall of blood vessels but are not found within the walls. Like perivascular cells, they express MHC class II
proteins even at low levels of inflammatory cytokine
activity. Unlike perivascular cells, but similar to resident microglia, juxtavascular microglia do not exhibit rapid turnover or replacement with myeloid precursor cells on a regular basis.
and the subcortical white matter
. This may explain why the majority of ameboid microglial cells are found within the "fountains of microglia" in the cerebral cortex
.
, bacteria
, or other foreign materials in the inflamed state. Once the microglial cell is "full" it stops phagocytic activity and changes into a relatively non-reactive gitter cell
.
'. Both of these chemicals can directly damage cells and lead to neuronal cell death. Proteases secreted by microglia catabolise specific proteins causing direct cellular damage, while cytokines like IL-1 promote demyelination of neuronal axons. Finally, microglia can injure neurons through NMDA receptor-mediated processes by secreting glutamate and aspartate. Cytotoxic secretion is aimed at destroying infected neurons, virus, and bacteria, but can also cause large amounts of collateral neural damage. As a result, chronic inflammatory response can result in large scale neural damage as the microglia ravage the brain in an attempt to destroy the invading infection.
, T-cells cross the blood-brain barrier
thanks to specialized surface markers and then directly bind to microglia in order to receive antigens. Once they have been presented with antigens, T-cells go on to fulfill a variety of roles including pro-inflammatory recruitment, formation of immunomemories, secretion of cytotoxic materials, and direct attacks on the plasma membranes of foreign cells.
in non-infected regions and promoting inflammation
in infected or damaged tissue. Microglia accomplish this through an extremely complicated series of extracellular signaling molecules which allow them to communicate with other microglia, astrocytes, nerves, T-cells, and myeloid progenitor cells. As mentioned above the cytokine
INF-γ can be used to activate microglial cells. In addition, after becoming activated with INF-γ, microglia also release more INF-γ into the extracellular space. This activates more microglia and starts a cytokine
induced activation cascade rapidly activating all nearby microglia. Microglia produced TNF-α causes neural tissue to undergo apoptosis
and increases inflammation
. IL-8
promotes B-cell growth and differentiation, allowing it to assist microglia in fighting infection. Another cytokine
, IL-1, inhibits the cytokines IL-10
and TGF-β, which downregulate antigen presentation
and pro-inflammatory signaling. Additional dendritic cells and T-cells are recruited to the site of injury through the microglial production of the chemotactic molecules like MDC, IL-8
, and MIP-3β. Finally, PGE2 and other prostanoids help prevent chronic inflammation by inhibiting microglial pro-inflammatory response and downregulating Th1
(T-helper cell) response.
(CNS) specific, inflammation-like glial responses that may produce neurodegenerative symptoms such as plaque
formation, dystrophic neurite
growth, and excessive tau phosphorylation. It is important to distinguish between acute and chronic neuroinflammation. Acute neuroinflammation is generally caused by some neuronal injury after which microglia migrate to the injured site engulfing dead cells and debris. The term neuroinflammation generally refers to more chronic, sustained injury when the responses of microglial cells contribute to and expand the neurodestructive effects, worsening the disease process.
When microglia are activated they take on an amoeboid
shape and they increase their gene expression. Increased gene expression leads to the production of numerous potentially neurotoxic mediators
. These mediators are important in the normal functions of microglia and their production is usually decreased once their task is complete. In chronic neuroinflammation, microglia remain activated for an extended period during which the production of mediators is sustained longer than usual. This increase in mediators contributes to neuronal death.
Neuroinflammation is unique from inflammation in other organs, but does include some similar mechanisms such as the localized production of chemoattractant molecules to the site of inflammation. The following list contains a few of the numerous substances that are secreted when microglia are activated:
and in vivo
. Chemokines are divided into four main subfamilies: C, CC, CXC, and CX3C. Microglial cells are sources of some chemokines and express the monocyte chemoattractant protein-1 (MCP-1) chemokine in particular. Other inflammatory cytokines like IL-1β and TNF-α, as well as bacterial-derived lipopolysaccharide
(LPS) may stimulate microglia to produce MCP-1, MIP-1α, and MIP-1β. Microglia can express CCR3, CCR5
, CXCR4, and CX3CR1
in vitro. Chemokines are proinflammatory and therefore contribute to the neuroinflammation process.
and neuronal cells that are in the neighborhood of the microglia releasing these compounds. These proteases include; cathepsins B, L, and S, the matrix metalloproteinases MMP-1, MMP-2, MMP-3, and MMP-9, and the metalloprotease-disintegrin ADAM8 plasminogen which forms outside microglia and degrades the extracellular matrix. Both Cathepsin B, MMP-1 and MMP-3 have been found to be increased in Alzheimer's disease
(AD) and cathepsin B is increased in multiple sclerosis
(MS). Elastase
, another protease, could have large negative effects on the extracellular matrix.
(APP) in response to excitotoxic
injury. Plaques
result from abnormal proteolytic cleavage of membrane bound APP. Amyloid plaques can stimulate microglia to produce neurotoxic compounds such as cytokines, excitotoxin, nitrite oxide and lipophylic amine
s, which all cause neural damage. Plaques in Alzheimer's disease contain activated microglia. A study has shown that direct injection of amyloid into brain tissue activates microglia, which reduces the number of neurons. Microglia have also been suggested as a possible source of secreted β amyloid.
to reduce the cell numbers back to baseline. Activation of microglia places a load on the anabolic and catabolic machinery of the cells causing activated microglia to die sooner than non-activated cells. To compensate for microglial loss over time, microglia undergo mitosis and bone marrow derived progenitor cells migrate into the brain via the meninges
and vasculature.
Accumulation of minor neuronal damage that occurs during normal aging can transform microglia into enlarged and activated cells. These chronic, age-associated increases in microglial activation and IL-1 expression may contribute to increased risk of Alzheimer's disease with advancing age through favoring neuritic plaque formation in susceptible patients. DNA damage might contribute to age-associated microglial activation. Another factor might be the accumulation of advanced glycation endproducts, which accumulate with aging. These proteins are strongly resistant to proteolytic processes and promote protein cross-linking.
Research has discovered dystrophic (defective development) human microglia. "These cells are characterized by abnormalities in their cytoplasmic structure, such as deramified, atrophic, fragmented or unusually tortuous processes, frequently bearing spheroidal or bulbous swellings." The incidence of dystrophic microglia increases with aging. Microglial degeneration and death have been reported in research on Prion disease, Schizophrenia
and Alzheimer's disease, indicating that microglial deterioration might be involved in neurodegenerative diseases. A complication of this theory is the fact that it is difficult to distinguish between "activated" and "dystrophic" microglia in the human brain.
(AD) is a progressive, neurodegenerative disease where the brain develops abnormal clumps (amyloid plaques) and tangled fiber bundles (neurofibrillary tangles).
There are many activated microglia over-expressing IL-1
in the brains of Alzheimer patients that are distributed with both αβ plaques and neurofibrillary tangles. This over expression of IL-1 leads to excessive tau phosphorylation that is related to tangle development in Alzheimer's disease.
Many activated microglia are found to be associated with amyloid deposits in the brains of Alzheimer's patients. Microglia interact with β-amyloid plaques through cell surface receptors that are linked to tyrosine kinase
based signaling cascades that induce inflammation. When microglia interact with the deposited fibrillar forms of β-amyloid it leads to the conversion of the microglia into an activated cell and results in the synthesis and secretion of cytokines and other proteins that are neurotoxic.
s (NSAIDs) have proven to be effective in reducing the risk of AD. "Sustained treatment with NSAIDs lowers the risk of AD by 55%, delays disease onset, attenuates symptomatic severity and slows the loss of cognitive abilities. The main cellular target for NSAIDs is thought to be microglia. This is supported by the fact that in patients taking NSAIDs the number of activated microglia is decreased by 65%."
is a movement disorder in which the dopamine
-producing neurons in the brain do not function as they should.
is an important element in the development of HIV
-associated dementia complex (HAD). The only brain cell type that is "productively" infected with the virus are microglial cells. It has also become clear that neurotoxic mediators released from brain microglia play an important role in the pathogenesis of HIV-1.
"HIV-1 can enter the microglial cell via CD4
receptors and chemokine co-receptors such as CCR3, CCR5, and CXCR4, with CCR5 being the most important of these. Interestingly, humans with double allelic loss of CCR5
are virtually immune to HIV acquired via the sexual route (though can be infected by IV transmission of CXCR4
tropic viruses). IL-4 and IL-10 enhance the entry and replication of HIV-1 in microglia through the up-regulation of CD4 and CCR5 expression, respectively. The chemokines CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β, all of which bind to CCR5, are inhibitory to HIV-1 replication in microglial cells, apparently by their ability to block viral entry."
Infected microglia contain viral particles intracellularly. There is a correlation between the severity of dementia and microglial production of neurotoxins.
One discrepancy in HAD is the limited number of HIV-1 infected microglia in comparison to the many CNS abnormalities that occur. This suggests that chemical factors that are released from microglial cells are contributing to neuronal loss. "It has become more and more apparent that HIV-1 infected microglial cells actively secrete both endogenous neurotoxins such as TNF-α, IL-1β, CXCL8/IL-8, glutamate, quinolinic acid, platelet activating factor, eicosanoids, and NO as well as the neurotoxic viral proteins Tat, gp120, and gp41."
Microglia are the main target of HIV-1 in the brain. When activated by HIV-1 or viral proteins, they secrete or induce other cells to secrete neurotoxic factors; this process is accompanied by neuronal dysfunction (HAD).
(HSV) can cause herpes encephalitis
in babies and immunocompetent adults. Studies have shown that long-term neuroimmune activation persists after the herpes infection in patients. Microglia produce cytokines that are toxic to neurons; this may be a mechanism underlying HSV-related CNS damage. It has been found that "active microglial cells in HSV encephalitis patients do persist for more than 12 months after antiviral treatment."
(LPS) is the major component of the outer membrane of a gram-negative
bacteria
l cell wall. LPS has been shown to activate microglia in vitro
and stimulates microglia to produce cytokines, chemokines, and prostaglandins. "Although LPS has been used as a classic activating agent, a recent study of rat microglia demonstrated that prolonged LPS exposure induces a distinctly different activated state from that in microglia acutely exposed to LPS."
is the most common cause of bacterial meningitis
. It is primarily localized to the subarachnoid space
while cytokines and chemokines are produced inside the blood brain barrier. Microglia interact with streptococcus via their TLR2 receptor; this interaction then activates microglia to produce nitric oxide which is neurotoxic. The inflammatory response, triggered by microglia, may cause intracerebral edema
.
is a parasite that causes malaria
in humans. A serious complication of malaria is cerebral malaria (CM). CM occurs when red blood cells break through the blood brain barrier causing microhemorrhages, ischemia
and glial cell growth. This can lead to microglial aggregates called Durck's granulomas. Recent research has indicated that microglia play a major role in the pathogenesis of CM.
(a tetracycline derivative) has shown down-regulation of microglial MAPK. Another promising treatment is CPI-1189, which induces cell death in a TNF α-inhibiting compound that also down-regulates MAPK. Recent study shows that nicergoline
(Sermion) suppresses the production of proinflammatory cytokines and superoxide anion by activated microglia.
, is expressed by microglia in the central nervous system. Fractalkine (CX3CL1) is the exclusive ligand for CX3CR1 and is made as a transmembrane glycoprotein
from which a chemokine can be released. Cardona, et al. stated in 2006 that "using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity." Further studies into how CX3CR1 regulates microglial neurotoxicity
could lead to new therapeutic strategies for neuroprotection.
and γ-secretase inhibitors. Currently the γ-secretase inhibitors are in phase II clinical trials as a treatment for Alzheimer's disease but they have immunosuppressive properties, which could limit their use. Another strategy involves increasing the antibodies against a fragment of amyloid. This treatment is also in phase II clinical trials for the treatment of Alzheimer's disease.
and sodium phenylacetate were found to inhibit TNF-α, IL-1β, and IL-6 in rat microglia. This shows that the mevalonate pathway plays a role in controlling the expression of cytokines in microglia and may be important in developing drugs to treat neurodegenerative diseases. Naltrexone may pose a solution to the inflammatory mediators produced by microglia. Although naltrexone's main action is to competitively bind to opioid receptors thereby upregulating the number of receptors; moverover, it is used to help patients with an opioid dependency. New research shows that low-dose naltrexone can inhibit cytokine synthesis of microglia cells. This mechanism is still in its infancy, but it has proven to help some patients suffering from fibromyalgia syndrome. Naltrexone shows more promise than GCSs because the GCSs inhibit immune system function, increase allergic reactions and, as the name implies, increase blood glucose levels.
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
that are the resident macrophages of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, and thus act as the first and main form of active immune defense in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS). Microglia constitute 20% of the total glial cell population within the brain. Microglia (and astrocytes) are distributed in large non-overlapping regions throughout the brain and spinal cord.
Microglia are constantly scavenging the CNS for damaged neurons, plaques, and infectious agents. The brain and spinal cord are considered "immune privileged" organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood-brain barrier, microglial cells must react quickly to decrease inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (few antibodies are small enough to cross the blood brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. They achieve this sensitivity in part by having unique potassium channels that respond to even small changes in extracellular potassium.
Origin
Microglial cells differentiate in the bone marrowBone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
from hematopoietic stem cells, the progenitors
Progenitor cell
A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target" cell...
of all blood cells. During hematopoiesis, some of these stem cells differentiate into 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 and travel from the bone marrow to the brain, where they settle and further differentiate into microglia.
Monocytes can also differentiate into myeloid dendritic cells and macrophages in the peripheral systems. Like macrophages in the rest of the body, microglia use phagocytic and cytotoxic mechanisms to destroy foreign materials. Microglia and macrophages both contribute to the immune response by acting as antigen presenting cells, as well as promoting inflammation and homeostatic mechanisms within the body by secreting cytokines and other signaling molecules.
In their downregulated form, microglia lack the MHC class I
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
/MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
proteins, IFN-γ cytokines, CD45 antigens
CD45
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen , which was originally called leukocyte common antigen.- Function :The protein encoded by this gene is a member of the protein tyrosine...
, and many other surface receptors required to act in the antigen-presenting, phagocytic, and cytotoxic roles that hallmark normal macrophages. Microglia also differ from macrophages in that they are much more tightly regulated spatially and temporally in order to maintain a precise immune response.
Another difference between microglia and other cells that differentiate from myeloid progenitor cells is the turnover rate. Macrophages and dendritic cells are constantly being used up and replaced by myeloid progenitor cells which differentiate into the needed type. Due to the blood brain barrier, it would be fairly difficult for the body to constantly replace microglia. Therefore, instead of constantly being replaced with myeloid progenitor cells, the microglia maintain their status quo while in their quiescent state, and then, when they are activated, they rapidly proliferate in order to keep their numbers up. Bone chimera studies have shown, however, that in cases of extreme infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
will weaken, and microglia will be replaced with haematogenous, cart-marrow derived cells, namely myeloid progenitor cells and macrophages. Once the infection has decreased the disconnect between peripheral and central systems is reestablished and only microglia are present for the recovery and regrowth period.
History
The ability to view and characterize different neural cells including microglia began in 1880 when Nissl staining was developed by Franz NisslFranz Nissl
Franz Nissl was a German medical researcher. He was a noted neuropathologist.-Early life:...
. Franz Nissl and F. Robertson first described microglial cells during their histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
experiments. The cell staining techniques in the 1880s showed that microglia are related to macrophages. The activation of microglia and formation of ramified microglial clusters was first noted by Victor Babeş
Victor Babes
Victor Babeș was a Romanian physician, biologist, and one of the earliest bacteriologists. He made early and significant contributions to the study of rabies, leprosy, diphtheria, tuberculosis, and other infectious diseases....
while studying a rabies
Rabies
Rabies is a viral disease that causes acute encephalitis in warm-blooded animals. It is zoonotic , most commonly by a bite from an infected animal. For a human, rabies is almost invariably fatal if post-exposure prophylaxis is not administered prior to the onset of severe symptoms...
case in 1897. Babeş noted the cells were found in a variety of viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
brain infections but did not know what the clusters of microglia he saw were. Pío del Río Hortega, a student of Santiago Ramón y Cajal
Santiago Ramón y Cajal
Santiago Ramón y Cajal ForMemRS was a Spanish pathologist, histologist, neuroscientist, and Nobel laureate. His pioneering investigations of the microscopic structure of the brain were original: he is considered by many to be the father of modern neuroscience...
, first called the cells "microglia" around 1920. He went on to characterize microglial response to brain lesions in 1927 and note the "fountains of microglia" present in the corpus callosum and other perinatal white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
areas in 1932. After many years of research Rio-Hortega became generally considered as the "Father of Microglia." For a long period of time little improvement was made in our knowledge of microglia. Then, in 1988, Hickey and Kimura showed that perivascular microglial cells are bone-marrow derived, and express high levels of MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
proteins used for antigen presentation. This confirmed Pio Del Rio-Hortega's postulate that microglial cells functioned similarly to macrophages by performing phagocytosis and antigen presentation
Antigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....
.
Types
Microglial cells are extremely plastic, and undergo a variety of structural changes based on their location and current role. This level of plasticity is required to fulfill the vast variety of immunological functions that microglia perform, as well as maintaining homeostasis within the brain. If microglia were not capable of this they would need to be replaced on a regular basis like macrophages, and would not be available to the CNS immune defense on extremely short notice without causing immunological imbalance under normal conditions.Ameboid
This form of microglial cell is found mainly within the perinatal white matterWhite matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
areas in the corpus callosum
Corpus callosum
The corpus callosum , also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication...
known as the "Fountains of Microglia." This shape allows the microglial free movement throughout the neural tissue, which allows it to fulfill its role as a scavenger cell. Ameboid microglia are able to phagocytose debris, but do not fulfill the same antigen-presenting and inflammatory roles as activated microglia. Ameboid microglia are especially prevalent during the development and rewiring of the brain, when there are large amounts of extracellular debris and apoptotic cells to remove.
Ramified
This form of microglial cell is commonly found at strategic locations throughout the entire brain and spinal cord in the absence of foreign material or dying cells. This "resting" form of microglia is composed of long branching processes and a small cellular body. Unlike the ameboid forms of microglia, the cell body of the ramified form remains fairly motionless, while its branches are constantly moving and surveying the surrounding area. The branches are very sensitive to small changes in physiological condition and require very specific culture conditions to observe in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
. Unlike activated or ameboid microglia, ramified microglia are unable to phagocytose cells and display little or no immunomolecules. This includes the MHC class I/II proteins normally used by macrophages and dendritic cells to present antigens to t-cells, and as a result ramified microglia function extremely poorly as antigen presenters. The purpose of this state is to maintain a constant level of available microglia to detect and fight infection, while maintaining an immunologically silent environment.
Non-phagocytic
This state is actually part of a graded response as microglia move from their ramified form to their fully active phagocytic form. Microglia can be activated by a variety of factors including: glutamate receptor agonists, pro-inflammatory cytokines, cell necrosisNecrosis
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...
factors, lipopolysaccharide, and changes in extracellular potassium (indicative of ruptured cells). Once activated the cells undergo several key morphological changes including the thickening and retraction of branches, uptake of MHC class I/II proteins, expression of immunomolecules, secretion of cytotoxic factors, secretion of recruitment molecules, and secretion of pro-inflammatory signaling molecules (resulting in a pro-inflammation signal cascade). Activated non-phagocytic microglia generally appear as "bushy," "rods," or small ameboids depending on how far along the ramified to full phagocytic transformation continuum they are. In addition, the microglia also undergo rapid proliferation in order to increase their numbers for the upcoming battle. From a strictly morphological perspective, the variation in microglial form along the continuum is associated with changing morphological complexity and can be quantitated using the methods of fractal analysis, which have proven sensitive to even subtle, visually undetectable changes associated with different morphologies in different pathological states.
Phagocytic
Activated phagocytic microglia are the maximally immune responsive form of microglia. These cells generally take on a large, ameboid shape, although some variance has been observed. In addition to having the antigen presenting, cytotoxic and inflammatoryInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
mediating signaling of activated non-phagocytic microglia, they are also able to phagocytose foreign materials and display the resulting immunomolecules for T-cell activation. Phagocytic microglia travel to the site of the injury, engulf the offending material, and secrete pro-inflammatory factors to promote more cells to proliferate and do the same. Activated phagocytic microglia also interact with astrocytes and neural cells to fight off the infection as quickly as possible with minimal damage to the healthy brain cells.
Gitter cells
Gitter cells are the eventual result of microglial cell's phagocytosis of infectious material. Eventually, after engulfing a certain amount of material, the phagocytic microglia becomes unable to phagocytose any further materials. The resulting cellular mass is known as a granular corpuscle, named for its ‘grainy' appearance. By looking at tissues stained to reveal gitter cells, scientists can see post-infection areas that have healed.Perivascular
Unlike the other types of microglia mentioned above, "perivascular" microglia refers to the location of the cell rather than its form/function. Perivascular microglia are mainly found encased within the walls of the basal laminaBasal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below....
. They perform normal microglial functions, but unlike normal microglia they are replaced by bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
derived precursor cells on a regular basis and express MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
antigens regardless of the outside environment. Perivascular microglia also react strongly to macrophage differentiation antigens. These microglia have been shown to be essential to repair of vascular
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...
walls, as shown by Ritter's experiments and observations on ischemic retinopathy. Perivascular microglia promote endothelial cell proliferation allowing new vessels to be formed and damaged vessels to be repaired. During repair and development, myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
recruitment and differentiation into microglial cells is highly accelerated to accomplish these tasks.
Juxtavascular
Like perivascular microglia, juxtavascular microglia can be distinguished mainly by their location. Juxtavascular microglia are found making direct contact with the basal laminaBasal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below....
wall of blood vessels but are not found within the walls. Like perivascular cells, they express MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
proteins even at low levels of inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
activity. Unlike perivascular cells, but similar to resident microglia, juxtavascular microglia do not exhibit rapid turnover or replacement with myeloid precursor cells on a regular basis.
Functions
Microglial cells fulfill an astonishing variety of different tasks within the CNS mainly related to both immune response and maintaining homeostasis. The following are some of the major known functions carried out by these cells.Scavenging
In addition to being very sensitive to small changes in their environment, each microglial cell also physically surveys its domain on a regular basis. This action is carried out in the ameboid and resting states. While moving through its set region, if the microglial cell finds any foreign material, damaged cells, apoptotic cells, neural tangles, DNA fragments, or plaques it will activate and phagocytose the material or cell. In this manner microglial cells also act as "housekeepers" cleaning up random cellular debris. During developmental wiring of the brain, microglial cells play a large role removing unwanted excess cellular matter. Post development, the majority of dead or apoptotic cells are found in the cerebral cortexCerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and the subcortical white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
. This may explain why the majority of ameboid microglial cells are found within the "fountains of microglia" in the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
.
Phagocytosis
The main role of microglia, phagocytosis, involves the engulfing of various materials. Engulfed materials generally consist of cellular debris, lipids, and apoptotic cells in the non-inflamed state, and invading virusVirus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, or other foreign materials in the inflamed state. Once the microglial cell is "full" it stops phagocytic activity and changes into a relatively non-reactive gitter cell
Gitter cell
A gitter cell or hortega cell is a microglial cell that is globular and swollen after having phagocytized debris from cells destroyed pathologically in the central nervous system. Also called compound granule cell or compound granular corpuscle....
.
Cytotoxicity
In addition to being able to destroy infectious organisms through cell to cell contact via phagocytosis, microglia can also release a variety of cytotoxic substances. Microglia in culture secrete large amounts of H2O2 and NO in a process known as ‘respiratory burstRespiratory burst
Respiratory burst is the rapid release of reactive oxygen species from different types of cells....
'. Both of these chemicals can directly damage cells and lead to neuronal cell death. Proteases secreted by microglia catabolise specific proteins causing direct cellular damage, while cytokines like IL-1 promote demyelination of neuronal axons. Finally, microglia can injure neurons through NMDA receptor-mediated processes by secreting glutamate and aspartate. Cytotoxic secretion is aimed at destroying infected neurons, virus, and bacteria, but can also cause large amounts of collateral neural damage. As a result, chronic inflammatory response can result in large scale neural damage as the microglia ravage the brain in an attempt to destroy the invading infection.
Antigen presentation
As mentioned above, resident non-activated microglia act as poor antigen presenting cells due to their lack of MHC class I/II proteins. Upon activation they rapidly uptake MHC class I/II proteins and quickly become efficient antigen presenters. In some cases, microglia can also be activated by IFN-γ to present antigens, but do not function as effectively as if they had undergone uptake of MHC class I/II proteins. During inflammationInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, T-cells cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
thanks to specialized surface markers and then directly bind to microglia in order to receive antigens. Once they have been presented with antigens, T-cells go on to fulfill a variety of roles including pro-inflammatory recruitment, formation of immunomemories, secretion of cytotoxic materials, and direct attacks on the plasma membranes of foreign cells.
Synaptic stripping
In a phenomenon first noticed in spinal lesions by Blinzinger and Kreutzberg in 1968, post-inflammation microglia remove the branches from nerves near damaged tissue. This helps promote regrowth and remapping of damaged neural circuitry.Promotion of repair
Post-inflammation, microglia undergo several steps to promote regrowth of neural tissue. These include synaptic stripping, secretion of anti-inflammatory cytokines, recruitment of neurons and astrocytes to the damaged area, and formation of gitter cells. Without microglial cells regrowth and remapping would be considerably slower in the resident areas of the CNS and almost impossible in many of the vascular systems surrounding the brain and eyes.Extracellular signaling
A large part of microglial cell's role in the brain is maintaining homeostasisHomeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
in non-infected regions and promoting inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
in infected or damaged tissue. Microglia accomplish this through an extremely complicated series of extracellular signaling molecules which allow them to communicate with other microglia, astrocytes, nerves, T-cells, and myeloid progenitor cells. As mentioned above the cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
INF-γ can be used to activate microglial cells. In addition, after becoming activated with INF-γ, microglia also release more INF-γ into the extracellular space. This activates more microglia and starts a cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
induced activation cascade rapidly activating all nearby microglia. Microglia produced TNF-α causes neural tissue to undergo 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 increases inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. IL-8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
promotes B-cell growth and differentiation, allowing it to assist microglia in fighting infection. Another cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
, IL-1, inhibits the cytokines IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
and TGF-β, which downregulate antigen presentation
Antigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....
and pro-inflammatory signaling. Additional dendritic cells and T-cells are recruited to the site of injury through the microglial production of the chemotactic molecules like MDC, IL-8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
, and MIP-3β. Finally, PGE2 and other prostanoids help prevent chronic inflammation by inhibiting microglial pro-inflammatory response and downregulating 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...
(T-helper cell) response.
Role in chronic neuroinflammation
The word neuroinflammation has come to stand for chronic, central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) specific, inflammation-like glial responses that may produce neurodegenerative symptoms such as plaque
Senile plaques
Senile plaques are extracellular deposits of amyloid in the gray matter of the brain. The deposits are associated with degenerative neural structures and an abundance of microglia and astrocytes...
formation, dystrophic neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
growth, and excessive tau phosphorylation. It is important to distinguish between acute and chronic neuroinflammation. Acute neuroinflammation is generally caused by some neuronal injury after which microglia migrate to the injured site engulfing dead cells and debris. The term neuroinflammation generally refers to more chronic, sustained injury when the responses of microglial cells contribute to and expand the neurodestructive effects, worsening the disease process.
When microglia are activated they take on an amoeboid
Amoeboid
Amoeboids are single-celled life-forms characterized by an irregular shape."Amoeboid" and "amœba" are often used interchangeably even by biologists, and especially refer to a creature moving by using pseudopodia. Most references to "amoebas" or "amoebae" are to amoeboids in general rather than to...
shape and they increase their gene expression. Increased gene expression leads to the production of numerous potentially neurotoxic mediators
Mediator (coactivator)
Mediator is a multiprotein complex that functions as a transcriptional coactivator. It was discovered by Roger D. Kornberg, winner of the 2006 Nobel Prize in Chemistry...
. These mediators are important in the normal functions of microglia and their production is usually decreased once their task is complete. In chronic neuroinflammation, microglia remain activated for an extended period during which the production of mediators is sustained longer than usual. This increase in mediators contributes to neuronal death.
Neuroinflammation is unique from inflammation in other organs, but does include some similar mechanisms such as the localized production of chemoattractant molecules to the site of inflammation. The following list contains a few of the numerous substances that are secreted when microglia are activated:
Cytokines
Microglia activate the proinflammatory cytokines IL-1α, IL-1β and TNF-α in the CNS. Cytokines play a potential role in neurodegeneration when microglia remain in a sustained activated state. Direct injection of the cytokines IL-1α, IL-1β and TNF-α into the CNS result in local inflammatory responses and neuronal degradation. This is in contrast with the potential neurotrophic (inducing growth of neurons) actions of these cytokines during acute neuroinflammation.Chemokines
Chemokines are cytokines that stimulate directional migration of inflammatory cells in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
. Chemokines are divided into four main subfamilies: C, CC, CXC, and CX3C. Microglial cells are sources of some chemokines and express the monocyte chemoattractant protein-1 (MCP-1) chemokine in particular. Other inflammatory cytokines like IL-1β and TNF-α, as well as bacterial-derived lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
(LPS) may stimulate microglia to produce MCP-1, MIP-1α, and MIP-1β. Microglia can express CCR3, CCR5
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
, CXCR4, and CX3CR1
CX3CR1
CX3C chemokine receptor 1 also known as the fractalkine receptor or G-protein coupled receptor 13 is a protein that in humans is encoded by the CX3CR1 gene...
in vitro. Chemokines are proinflammatory and therefore contribute to the neuroinflammation process.
Proteases
When microglia are activated they induce the synthesis and secretion of proteolytic enzymes that are potentially involved in many functions. There are a number of proteases that possess the potential to degrade both the extracellular matrixExtracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
and neuronal cells that are in the neighborhood of the microglia releasing these compounds. These proteases include; cathepsins B, L, and S, the matrix metalloproteinases MMP-1, MMP-2, MMP-3, and MMP-9, and the metalloprotease-disintegrin ADAM8 plasminogen which forms outside microglia and degrades the extracellular matrix. Both Cathepsin B, MMP-1 and MMP-3 have been found to be increased in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD) and cathepsin B is increased in multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
(MS). Elastase
Elastase
In molecular biology, elastase is an enzyme from the class of proteases that break down proteins.- Forms and classification:There exist eight human genes for elastase:Bacterial forms: Organisms such as P...
, another protease, could have large negative effects on the extracellular matrix.
Amyloid precursor protein
Microglia synthesize amyloid precursor proteinAmyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
(APP) in response to excitotoxic
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
injury. Plaques
Senile plaques
Senile plaques are extracellular deposits of amyloid in the gray matter of the brain. The deposits are associated with degenerative neural structures and an abundance of microglia and astrocytes...
result from abnormal proteolytic cleavage of membrane bound APP. Amyloid plaques can stimulate microglia to produce neurotoxic compounds such as cytokines, excitotoxin, nitrite oxide and lipophylic amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s, which all cause neural damage. Plaques in Alzheimer's disease contain activated microglia. A study has shown that direct injection of amyloid into brain tissue activates microglia, which reduces the number of neurons. Microglia have also been suggested as a possible source of secreted β amyloid.
Aging
Microglia undergo a burst of mitotic activity during injury; this proliferation is followed by apoptosisApoptosis
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...
to reduce the cell numbers back to baseline. Activation of microglia places a load on the anabolic and catabolic machinery of the cells causing activated microglia to die sooner than non-activated cells. To compensate for microglial loss over time, microglia undergo mitosis and bone marrow derived progenitor cells migrate into the brain via the meninges
Meninges
The meninges is the system of membranes which envelopes the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.-Dura...
and vasculature.
Accumulation of minor neuronal damage that occurs during normal aging can transform microglia into enlarged and activated cells. These chronic, age-associated increases in microglial activation and IL-1 expression may contribute to increased risk of Alzheimer's disease with advancing age through favoring neuritic plaque formation in susceptible patients. DNA damage might contribute to age-associated microglial activation. Another factor might be the accumulation of advanced glycation endproducts, which accumulate with aging. These proteins are strongly resistant to proteolytic processes and promote protein cross-linking.
Research has discovered dystrophic (defective development) human microglia. "These cells are characterized by abnormalities in their cytoplasmic structure, such as deramified, atrophic, fragmented or unusually tortuous processes, frequently bearing spheroidal or bulbous swellings." The incidence of dystrophic microglia increases with aging. Microglial degeneration and death have been reported in research on Prion disease, Schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and Alzheimer's disease, indicating that microglial deterioration might be involved in neurodegenerative diseases. A complication of this theory is the fact that it is difficult to distinguish between "activated" and "dystrophic" microglia in the human brain.
Role of microglia in neurodegeneration
Neurodegenerative disorders are characterized by progressive cell loss in specific neuronal populations. "Many of the normal trophic functions of glia may be lost or overwhelmed when the cells become chronically activated in progressive neurodegenerative disorders, for there is abundant evidence that in such disorders, activated glia play destructive roles by direct and indirect inflammatory attack." The following are prominent examples of microglial cells' role in neurodegenerative disorders.Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD) is a progressive, neurodegenerative disease where the brain develops abnormal clumps (amyloid plaques) and tangled fiber bundles (neurofibrillary tangles).
There are many activated microglia over-expressing IL-1
IL-1
IL-1 may refer to:* Interleukin 1, a protein* Illinois' 1st congressional district* Illinois Route 1* Building 1 of Infinite Loop , the Headquarters of Apple Inc....
in the brains of Alzheimer patients that are distributed with both αβ plaques and neurofibrillary tangles. This over expression of IL-1 leads to excessive tau phosphorylation that is related to tangle development in Alzheimer's disease.
Many activated microglia are found to be associated with amyloid deposits in the brains of Alzheimer's patients. Microglia interact with β-amyloid plaques through cell surface receptors that are linked to tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
based signaling cascades that induce inflammation. When microglia interact with the deposited fibrillar forms of β-amyloid it leads to the conversion of the microglia into an activated cell and results in the synthesis and secretion of cytokines and other proteins that are neurotoxic.
Treatment
Non-steroidal anti-inflammatory drugNon-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s (NSAIDs) have proven to be effective in reducing the risk of AD. "Sustained treatment with NSAIDs lowers the risk of AD by 55%, delays disease onset, attenuates symptomatic severity and slows the loss of cognitive abilities. The main cellular target for NSAIDs is thought to be microglia. This is supported by the fact that in patients taking NSAIDs the number of activated microglia is decreased by 65%."
Parkinson's disease
Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
is a movement disorder in which the dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
-producing neurons in the brain do not function as they should.
Cardiovascular Diseases
Recently microglial activation has been reported in rats with myocardial infarction (Rana et al.,2010). These activation was specific to brain nuclei involved in cardiovascular regulation suggesting possible role of microglial activation in pathogenesis of heart failure.Human immunodeficiency virus
The infection of mononuclear phagocytes with HIV-1HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
is an important element in the development of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-associated dementia complex (HAD). The only brain cell type that is "productively" infected with the virus are microglial cells. It has also become clear that neurotoxic mediators released from brain microglia play an important role in the pathogenesis of HIV-1.
"HIV-1 can enter the microglial cell via CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
receptors and chemokine co-receptors such as CCR3, CCR5, and CXCR4, with CCR5 being the most important of these. Interestingly, humans with double allelic loss of CCR5
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
are virtually immune to HIV acquired via the sexual route (though can be infected by IV transmission of CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
tropic viruses). IL-4 and IL-10 enhance the entry and replication of HIV-1 in microglia through the up-regulation of CD4 and CCR5 expression, respectively. The chemokines CCL5/RANTES, CCL3/MIP-1α, CCL4/MIP-1β, all of which bind to CCR5, are inhibitory to HIV-1 replication in microglial cells, apparently by their ability to block viral entry."
Infected microglia contain viral particles intracellularly. There is a correlation between the severity of dementia and microglial production of neurotoxins.
One discrepancy in HAD is the limited number of HIV-1 infected microglia in comparison to the many CNS abnormalities that occur. This suggests that chemical factors that are released from microglial cells are contributing to neuronal loss. "It has become more and more apparent that HIV-1 infected microglial cells actively secrete both endogenous neurotoxins such as TNF-α, IL-1β, CXCL8/IL-8, glutamate, quinolinic acid, platelet activating factor, eicosanoids, and NO as well as the neurotoxic viral proteins Tat, gp120, and gp41."
Microglia are the main target of HIV-1 in the brain. When activated by HIV-1 or viral proteins, they secrete or induce other cells to secrete neurotoxic factors; this process is accompanied by neuronal dysfunction (HAD).
Herpes simplex virus
Herpes simplex virusHerpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
(HSV) can cause herpes encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
in babies and immunocompetent adults. Studies have shown that long-term neuroimmune activation persists after the herpes infection in patients. Microglia produce cytokines that are toxic to neurons; this may be a mechanism underlying HSV-related CNS damage. It has been found that "active microglial cells in HSV encephalitis patients do persist for more than 12 months after antiviral treatment."
Role in bacterial infections
LipopolysaccharideLipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
(LPS) is the major component of the outer membrane of a gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l cell wall. LPS has been shown to activate microglia in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and stimulates microglia to produce cytokines, chemokines, and prostaglandins. "Although LPS has been used as a classic activating agent, a recent study of rat microglia demonstrated that prolonged LPS exposure induces a distinctly different activated state from that in microglia acutely exposed to LPS."
Streptococcus pneumoniae
Streptococcus pneumoniaeStreptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...
is the most common cause of bacterial meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
. It is primarily localized to the subarachnoid space
Subarachnoid space
In the central nervous system, the subarachnoid cavity is the interval between the arachnoid membrane and pia mater....
while cytokines and chemokines are produced inside the blood brain barrier. Microglia interact with streptococcus via their TLR2 receptor; this interaction then activates microglia to produce nitric oxide which is neurotoxic. The inflammatory response, triggered by microglia, may cause intracerebral edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
.
Plasmodium falciparum
Plasmodium falciparumPlasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
is a parasite that causes malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
in humans. A serious complication of malaria is cerebral malaria (CM). CM occurs when red blood cells break through the blood brain barrier causing microhemorrhages, ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
and glial cell growth. This can lead to microglial aggregates called Durck's granulomas. Recent research has indicated that microglia play a major role in the pathogenesis of CM.
Inhibition of activation
One way to control neuroinflammation is to inhibit microglial activation. Studies on microglia have shown that they are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (MAPK). Previous approaches to down-regulate activated microglia focused on immunosuppressants. Recently, minocyclineMinocycline
Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...
(a tetracycline derivative) has shown down-regulation of microglial MAPK. Another promising treatment is CPI-1189, which induces cell death in a TNF α-inhibiting compound that also down-regulates MAPK. Recent study shows that nicergoline
Nicergoline
Nicergoline is an ergot derivative used to treat senile dementia and other disorders with vascular origins. It has been found to increase mental agility and enhance clarity and perception. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of...
(Sermion) suppresses the production of proinflammatory cytokines and superoxide anion by activated microglia.
Regulation of chemokine receptor
The chemokine receptor, CX3CR1CX3CR1
CX3C chemokine receptor 1 also known as the fractalkine receptor or G-protein coupled receptor 13 is a protein that in humans is encoded by the CX3CR1 gene...
, is expressed by microglia in the central nervous system. Fractalkine (CX3CL1) is the exclusive ligand for CX3CR1 and is made as a transmembrane glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
from which a chemokine can be released. Cardona, et al. stated in 2006 that "using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity." Further studies into how CX3CR1 regulates microglial neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
could lead to new therapeutic strategies for neuroprotection.
Inhibition of amyloid deposition
Inhibitors of amyloid deposition include the enzymes responsible for the production of extracellular amyloid such as β-secretaseBeta-secretase
Beta-secretase 1 also known as beta-site APP cleaving enzyme 1 , memapsin-2 , and aspartyl protease 2 is an enzyme that in humans is encoded by the BACE1 gene.β-Secretase is an aspartic-acid protease important in the pathogenesis of Alzheimer's disease,...
and γ-secretase inhibitors. Currently the γ-secretase inhibitors are in phase II clinical trials as a treatment for Alzheimer's disease but they have immunosuppressive properties, which could limit their use. Another strategy involves increasing the antibodies against a fragment of amyloid. This treatment is also in phase II clinical trials for the treatment of Alzheimer's disease.
Inhibition of cytokine synthesis
Glucocorticosteroids (GCS) are anti-inflammatory steroids that inhibit both central and peripheral cytokine synthesis and action. In a study conducted by Kalipada Pahan from the Department of Pediatrics at the Medical University of South Carolina, both lovastatinLovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
and sodium phenylacetate were found to inhibit TNF-α, IL-1β, and IL-6 in rat microglia. This shows that the mevalonate pathway plays a role in controlling the expression of cytokines in microglia and may be important in developing drugs to treat neurodegenerative diseases. Naltrexone may pose a solution to the inflammatory mediators produced by microglia. Although naltrexone's main action is to competitively bind to opioid receptors thereby upregulating the number of receptors; moverover, it is used to help patients with an opioid dependency. New research shows that low-dose naltrexone can inhibit cytokine synthesis of microglia cells. This mechanism is still in its infancy, but it has proven to help some patients suffering from fibromyalgia syndrome. Naltrexone shows more promise than GCSs because the GCSs inhibit immune system function, increase allergic reactions and, as the name implies, increase blood glucose levels.
External links
- Microglia home page at microglia.net
- The Role of Microglia in the Central Nervous System - Clinical Microbiology Reviews October 2004, p. 942-964, Vol. 17, No. 4
- Creeping into your Head - A Brief Introduction to Microglia - A Review from the Science Creative Quarterly - from Harvard UniversityHarvard UniversityHarvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
- The Department of Neuroscience at Wikiversity
- NIF Search - Microglial Cell via the Neuroscience Information FrameworkNeuroscience Information FrameworkThe Neuroscience Information Framework is a repository of global neuroscience web resources, including experimental, clinical, and translational neuroscience databases, knowledge bases, atlases, and genetic/genomic resources.-Description:...