Microglia

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Microglia
Microglia in resting state from rat cortex before traumatic brain injury (lectin staining with HRP)
Microglia/macrophage – activated form from rat cortex after traumatic brain injury (lectin staining with HRP)
Details
PrecursorPrimitive yolk-sac derived macrophage
SystemCentral nervous system
Identifiers
MeSHD017628
THH2.00.06.2.00004, H2.00.06.2.01025
FMA54539
Anatomical terms of microanatomy

Microglia are a type of

extracellular potassium.[7] Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions.[9] Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.[10]

The brain and spinal cord, which make up the CNS, are not usually accessed directly by pathogenic factors in the body's circulation due to a series of

T-cells
.

History

The ability to view and characterize different neural cells including microglia began in 1880 when Nissl staining was developed by

macrophages by performing phagocytosis and antigen presentation.[citation needed
]

Forms

Rat microglia grown in tissue culture in green, along with nerve fiber processes shown in red.
Microglia in rat cerebellar molecular layer in red, stained with antibody to IBA1/AIF1. Bergmann glia processes are shown in green, DNA in blue.

Microglial cells are extremely

macrophages, which must be replaced on a regular basis, and provides them the ability to defend the CNS on extremely short notice without causing immunological disturbance.[7] Microglia adopt a specific form, or phenotype, in response to the local conditions and chemical signals they have detected.[15]

Ramified

This form of microglial cell is commonly found at specific 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 amoeboid forms of microglia, the cell body of the ramified form remains in place 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 vitro.[15]

Unlike activated or ameboid microglia, ramified microglia do not phagocytose cells and secrete fewer immunomolecules (including the MHC class I/II proteins). Microglia in this state are able to search for and identify immune threats while maintaining homeostasis in the CNS.[16][17][18] Although this is considered the resting state, microglia in this form are still extremely active in chemically surveying the environment. Ramified microglia can be transformed into the activated form at any time in response to injury or threat.[15]

Reactive (Activated)

Although historically frequently used, the term "activated" microglia should be replaced by "reactive" microglia.

Iba1, which is upregulated in reactive microglia, is often used to visualize these cells.[20]

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: pro-inflammatory

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. 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.[7][16][17][21]

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,

astrocytes and neural cells to fight off any infection or inflammation as quickly as possible with minimal damage to healthy brain cells.[7][16]

Amoeboid

This shape allows the microglia free movement throughout the neural tissue, which allows it to fulfill its role as a scavenger cell. Amoeboid microglia are able to phagocytose debris, but do not fulfill the same antigen-presenting and inflammatory roles as activated microglia. Amoeboid 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. This form of microglial cell is found mainly within the perinatal white matter areas in the corpus callosum known as the "Fountains of Microglia".[7][17][22]

Gitter cells

Gitter cells are the eventual result of microglial cells' phagocytosis of infectious material or cellular debris. Eventually, after engulfing a certain amount of material, the phagocytic microglial cell 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 tissue stained to reveal gitter cells, pathologists can visualize healed areas post-infection.[23]

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

myeloid recruitment and differentiation into microglial cells is highly accelerated to accomplish these tasks.[24]

Juxtavascular

Like perivascular microglia, juxtavascular microglia can be distinguished mainly by their location. Juxtavascular microglia are found making direct contact with the

myeloid precursor cells on a regular basis.[7]

Functions

Activation of microglia via purinergic signalling

Microglial cells fulfill a 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.[citation needed]

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,

plaques it will activate and phagocytose the material or cell. In this manner microglial cells also act as "housekeepers", cleaning up random cellular debris.[16] During developmental wiring of the brain, microglial cells play a large role regulating numbers of neural precursor cells and removing apoptotic neurons. There is also evidence that microglia can refine synaptic circuitry by engulfing and eliminating synapses.[26] Post development, the majority of dead or apoptotic cells are found in the cerebral cortex 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.[22]

Phagocytosis

The main role of microglia,

gitter cell.[27]

Extracellular signaling

A large part of microglial cell's role in the brain is maintaining

chronic inflammation by inhibiting microglial pro-inflammatory response and downregulating Th1 (T-helper cell) response.[16]

Antigen presentation

As mentioned above, resident non-activated microglia act as poor

cytotoxic materials, and direct attacks on the plasma membranes of foreign cells.[7][16]

Cytotoxicity

In addition to being able to destroy infectious organisms through cell to cell contact via

aspartate and quinolinic acid. 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.[7] Edaravone, a radical scavenger, precludes oxidative neurotoxicity precipitated by activated microglia.[29]

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.[7] It has also been shown that microglia are involved in the process of synaptic pruning during brain development.[30]

Promotion of repair

Post-inflammation, microglia undergo several steps to promote regrowth of neural tissue. These include synaptic stripping, secretion of anti-inflammatory

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.[7][24] Recent research verified, that microglial processes constantly monitor neuronal functions through specialized somatic junctions, and sense the "well-being" of nerve cells. Via this intercellular communication pathway, microglia are capable of exerting robust neuroprotective effects, contributing significantly to repair after brain injury.[10] Microglia have also been shown to contribute to proper brain development, through contacting immature, developing neurons.[31]

Development

Origin and emergence of microglia in the CNS

For a long time it was thought that microglial cells differentiate in the bone marrow from hematopoietic stem cells, the progenitors of all blood cells. However, recent studies show that microglia originate in the yolk sac during a remarkably restricted embryonal period and populate the brain parenchyma guided by a precisely orchestrated molecular process.[4] Yolk sac progenitor cells require activation colony stimulating factor 1 receptor (CSF1R) for migration into the brain and differentiation into microglia.[32] Additionally, the greatest contribution to microglial repopulation is based upon its local self-renewal, both in steady state and disease, while circulating monocytes may also contribute to a lesser extent, especially in disease.[4][33]

Monocytes can also differentiate into

cytokines and other signaling molecules.[34]

In their downregulated form, microglia lack the

cytotoxic roles that distinguish 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.[16]

Another difference between microglia and other cells that differentiate from myeloid progenitor cells is the turnover rate. Macrophages and

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.[35]

Aging

Microglia undergo a burst of

progenitor cells migrate into the brain via the meninges and vasculature.[36]

Accumulation of minor neuronal damage that occurs during normal aging can transform microglia into enlarged and activated cells.

advanced glycation endproducts, which accumulate with aging.[37] These proteins are strongly resistant to proteolytic processes and promote protein cross-linking.[37]

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."

Prion disease, Schizophrenia and Alzheimer's disease, indicating that microglial deterioration might be involved in neurodegenerative diseases.[36] A complication of this theory is the fact that it is difficult to distinguish between "activated" and "dystrophic" microglia in the human brain.[36]

In mice, it has been shown that CD22 blockade restores homeostatic microglial phagocytosis in aging brains.[38]

image of microglia

Clinical significance

Main article: Role of microglia in disease
Step-by-step guide for analyzing microglia phenotypes

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells. As part of their response they secrete cytokines, chemokines, prostaglandins, and reactive oxygen species, which help to direct the immune response. Additionally, they are instrumental in the resolution of the inflammatory response, through the production of anti-inflammatory cytokines. Microglia have also been extensively studied for their harmful roles in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, as well as cardiac diseases, glaucoma, and viral and bacterial infections. There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS).[39]

Since microglia rapidly react to even subtle alterations in central nervous system homeostasis, they can be seen as sensors for neurological dysfunctions or disorders.[40] In the event of brain pathologies, the microglial phenotype is certainly altered.[40] Therefore, analyzing microglia can be a sensitive tool to diagnose and characterize central nervous system disorders in any given tissue specimen.[40] In particular, the microglial cell density, cell shape, distribution pattern, distinct microglial phenotypes and interactions with other cell types should be evaluated.[40]

Sensome genetics

The microglial sensome is a relatively new biological concept that appears to be playing a large role in

transmembrane proteins on the plasma membrane that are more highly expressed in microglia compared to neurons. It does not include secreted proteins or transmembrane proteins specific to membrane bound organelles, such as the nucleus, mitochondria, and endoplasmic reticulum.[41] The plurality of identified sensome genes code for pattern recognition receptors, however, there are a large variety of included genes. Microglial share a similar sensome to other macrophages, however they contain 22 unique genes, 16 of which are used for interaction with endogenous ligands. These differences create a unique microglial biomarker that includes over 40 genes including P2ry12 and HEXB. DAP12 (TYROBP) appears to play an important role in sensome protein interaction, acting as a signalling adaptor and a regulatory protein.[41]

The regulation of genes within the sensome must be able to change in order to respond to potential harm. Microglia can take on the role of neuroprotection or neurotoxicity in order to face these dangers.[42] For these reasons, it is suspected that the sensome may be playing a role in neurodegeneration. Sensome genes that are upregulated with aging are mostly involved in sensing infectious microbial ligands while those that are downregulated are mostly involved in sensing endogenous ligands.[41] This analysis suggests a glial-specific regulation favoring neuroprotection in natural neurodegeneration. This is in contrast to the shift towards neurotoxicity seen in neurodegenerative diseases.

The sensome can also play a role in neurodevelopment. Early-life brain infection results in microglia that are hypersensitive to later immune stimuli. When exposed to infection, there is an upregulation of sensome genes involved in neuroinflammation and a downregulation of genes that are involved with neuroplasticity.[43] The sensome's ability to alter neurodevelopment may however be able to combat disease. The deletion of CX3CL1, a highly expressed sensome gene, in rodent models of Rett syndrome resulted in improved health and longer lifespan.[44] The downregulation of Cx3cr1 in humans without Rett syndrome is associated with symptoms similar to schizophrenia.[45] This suggests that the sensome not only plays a role in various developmental disorders, but also requires tight regulation in order to maintain a disease-free state.

See also

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Further reading

External links

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