Microglia are a type of glia located throughout the brain and spinal cord of the central nervous system (CNS).[Kierdorf and Prinz, J Clin Invest. 2017;127(9): 3201–09. .] Microglia also constantly monitor neuronal functions through direct somatic contacts via their microglial processes, and exert neuroprotective effects when needed.
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 endothelial cells known as the blood–brain barrier, or BBB. The BBB 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 lack 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.
History
The ability to view and characterize different neural cells including microglia began in 1880 when Nissl staining was developed by
Franz Nissl. Franz Nissl and William Ford 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
Virus brain infections but did not know what the clusters of microglia he saw were.
The Spanish scientist Santiago Ramón y Cajal defined a "third element" (cell type) besides neurons and astrocytes.
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.
At the end of the 20th century, the experimental psychology group at Oxford University classified microglial cells into 3 types according to their morphology, tissue location and duration of phagocytic activity.
Forms
Microglial cells are extremely
neuroplasticity, and undergo a variety of structural changes based on location and system needs. This level of plasticity is required to fulfill the vast variety of functions that microglia perform. The ability to transform distinguishes microglia from
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.
Microglia adopt a specific form, or
phenotype, in response to the local conditions and chemical signals they have detected.
It has also been shown, that tissue-injury related ATP signalling plays a crucial role in the phenotypic transformation of microglia.
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.
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.
Reactive (activated)
Although historically frequently used, the term "activated" microglia should be replaced by "reactive" microglia.
Indeed, apparently quiescent microglia are not devoid of active functions and the "activation" term is misleading as it tends to indicate an "all or nothing" polarization of cell reactivity. The marker Iba1, which is upregulated in reactive microglia, is often used to visualize these cells.
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
cytokines, cell
necrosis 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. 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 inflammation-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 any infection or inflammation as quickly as possible with minimal damage to healthy brain cells.
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
apoptosis 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".
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 however often confused with perivascular macrophages (PVMs),
which are found encased within the walls of the
basal lamina, so care must be taken to determine which of these two cell types authors of publications are referring to. PVMs, unlike normal microglia, are replaced by
bone marrow-derived precursor cells on a regular basis, and express MHC class II antigens regardless of their environment.
Juxtavascular
"Perivascular microglia" and "juxtavascular microglia" are different names for the same type of cell. Confusion has arisen due to the misuse of the term perivascular microglia to refer to perivascular macrophages,
[ which are a different type of cell. Juxtavascular microglia/perivascular microglia are found making direct contact with the basal lamina wall of blood vessels but are not found within the walls. In this position they can interact with both endothelial cells and .]
Functions
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.
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 via highly motile microglial processes.
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 virus, 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.
Extracellular signaling
A large part of microglial cell's role in the brain is maintaining homeostasis 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, Neuron, T-cells, and myeloid progenitor cells. As mentioned above the cytokine IFN-γ can be used to activate microglial cells. In addition, after becoming activated with IFN-γ, microglia also release more IFN-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 prevent chronic inflammation by inhibiting microglial pro-inflammatory response and downregulating Th1 (T-helper cell) response.
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 express 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 inflammation, 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.
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.
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.
Development
For a long time it was thought that microglial cells differentiate in the bone marrow from hematopoietic stem cells, the Progenitor cell 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.
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 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.
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, 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.
Aging
Microglia undergo a burst of mitotic activity during injury; this proliferation is followed by apoptosis to reduce the cell numbers back to baseline.
Accumulation of minor neuronal damage that occurs during normal aging can transform microglia into enlarged and activated cells.
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."
In mice, it has been shown that CD22 blockade restores homeostatic microglial phagocytosis in aging brains.
Clinical significance
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 PANDAS.[ ] In the event of brain pathologies, the microglial phenotype is certainly altered.
Sensome genetics
The microglial sensome is a relatively new biological concept that appears to be playing a large role in neurodevelopment and neurodegeneration. The sensome refers to the unique grouping of protein transcripts used for sensing and microorganism. In other words, the sensome represents the genes required for the proteins used to sense molecules within the body. The sensome can be analyzed with a variety of methods including qPCR, RNA-seq, DNA microarray, and direct RNA sequencing. Genes included in the sensome code for receptors and transmembrane proteins on the cell 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 cell nucleus, mitochondrion, and endoplasmic reticulum.
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.[Block, ML, Zecca, L & Hong, JS. "Microglia-mediated neurotoxicity: uncovering the molecular mechanisms". Nat. Rev. Neurosci. 8, 57–69 (2007).] 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.
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.
See also
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Neuroimmune system
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List of human cell types derived from the germ layers
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List of distinct cell types in the adult human body
Further reading
External links
