Microglia
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2008-07-13T01:26:53Z
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/* Synaptic Stripping: */ Grammar
[[Image:Mikroglej 1.jpg|thumb|Microglia cells positive for [[lectins]] ]]
'''Microglia''' are a type of [[glial cell]] that acts 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. Unlike [[astrocytes]], individual microglia are distributed in large non-overlapping regions throughout the brain and spine.<ref name="Kreutzberg 1995">{{cite journal | author = Kreutzberg GW | title = The First Line of Defense in Brain Pathologies | journal = Drug-Research | volume = 45 | issue = 1 | pages = 357–360 | year = 1995 | pmid = 7763326}}</ref> Microglia are constantly moving and analyzing the CNS for damaged neurons, plaques, and infectious agents.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref> The brain and spine 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 increase [[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 (antibodies are too large 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.<ref name= "Dissing-Olesen 2007">{{cite journal | author = Dissing-Olesen L, Ladeby L, Nielsen HH, Toft-Hansen H, Dalmau I, Finsen B | title = Axonal lesion-induced microglial proliferation and microglial cluster formation in the mouse | journal = Neuroscience | volume = 149 | issue= 1 | pages = 112–122 | year = 2007 | pmid = 17870248 | doi = 10.1016/j.neuroscience.2007.06.037 }}</ref> They achieve this sensitivity in part by having unique [[potassium channels]] that respond to even small changes in extracellular potassium.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref>
==Origin==
Microglial cells differentiate from [[myeloid progenitor cells]], which are normally found in the [[bone marrow]]. During early development, a group of myeloid progenitor cells travel from the newly formed [[bone marrow]] to the brain where they settle and differentiate.<ref name= "Ritter 2006">{{cite journal | author = Ritter MR, Banin E, Moreno SK, Aguilar E, Dorrel MI, Friedlander M, | title = Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy | journal = Journal of Clinical Investination | volume = 116 | issue= 12 | pages = 3266–3276 | year = 2006 | pmid = 17111048 | doi = 10.1172/JCI29683 }}</ref> Myeloid progenitor cells can also differentiate into [[dendritic cells]] and [[macrophages]] in the peripheral systems. Similar to [[macrophages]] in the rest of the body, microglia primarily use [[phagocytic]] and [[cytotoxic]] mechanisms to destroy foreign materials. Microglia and [[macrophages]] both contribute to pro-inflammation and homeostatic mechanisms within the body through the secretion of [[cytokines]] and other signaling molecules. They are also both [[antigen-presenting cells]], however, macrophages are considered “professional” antigen presenting cells because they are always ready and able to act in this capacity, while microglial cells are considered “non-professional” because they must be “activated” prior to antigen presentation or [[phagocytosis]]. 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 the 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. <ref name= "Aloisi 2001">{{cite journal | author = Aloisi F | title = Immune Function of Microglia | journal = Glia | volume = 36 | pages = 165–179 | year = 2001 | pmid = 11596125 | doi = 10.1002/glia.1106 }}</ref>
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, bone-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.<ref name= "Gehrmann 1996">{{cite journal | author = Gehrmann J | title = Microglia: a sensor to threats in the nervous system? | journal = Research in Virology | volume = 147 | pages = 79–88 | year = 1996 | pmid = 8901425 | doi = 10.1016/0923-2516(96)80220-2 }}</ref>
==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 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 Babes while studying a [[rabies]] case in 1897. Babes noted the cells were found in a variety of [[Virus|viral]] brain infections but did not know what the clusters of microglia he saw were.<ref name= "Babes 1892">{{cite journal | author = Babes VS | title = Certains caractères des lesions histologiques de la rage | journal = Ann Inst Pasteur Lille | volume = 6 | pages = 209–223 | year = 1892 }}</ref> Pio del Rio-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.”<ref name= "Rio-Hortega 1892">{{cite journal | author = del Rio-Hortega P, Penfield W | title = Cerebral Cicatrix: the Reaction of Neuroglia and Microglia to Brain Wounds | journal = Bulletin of the Johns Hopkins Hospital | volume = 41 | pages = 278–303 | year = 1892 }}</ref> <ref name= "Rio-Hortega 1937">{{cite journal | author = del Rio-Hortega P | title = Microglia | journal = Cytology and Cellular Pathology of the Nervous System | pages = 481–534 | year = 1937 }}</ref> 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 undergoing [[phagocytosis]] and [[antigen presentation]].
==Types of Microglia==
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.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref>
====Ameboid:====
This form of microglial cell is found mainly within the perinatal [[white matter]] 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.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref> <ref name= "Ferrer 1990">{{cite journal | author = Ferrer I, Bernet E, Soriano E, Del Rio T, Fonseca M | title = Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes | journal = Neuroscience | volume = 39 | pages = 451–458 | year = 1990 | pmid = 2087266 | doi = 10.1016/0306-4522(90)90281-8 }}</ref><ref name= "Christensen 2006">{{cite journal | author = Christensen RN, Ha BK, Sun F, Bresnahan JC, Michael SB. | title = Kainate Induces Rapid Redistribution of the Actin Cytoskeleton in Ameboid Microglia | journal = Journal of Neuroscience Research | volume = 84 | pages = 170–181 | year = 2006 | pmid = 16625662 | doi = 10.1002/jnr.20865 }}</ref>
====Ramified (Quiescent):====
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 vitro]]. 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.<ref name=
"Christensen 2006">{{cite journal | author = Christensen RN, Ha BK, Sun F, Bresnahan JC, Michael SB. | title = Kainate Induces Rapid Redistribution of the Actin Cytoskeleton in Ameboid Microglia | journal = Journal of Neuroscience Research | volume = 84 | pages = 170–181 | year = 2006 | pmid = 16625662 | doi = 10.1002/jnr.20865 }}</ref> <ref name= "Aloisi 2001">{{cite journal | author = Aloisi F | title = Immune Function of Microglia | journal = Glia | volume = 36 | pages = 165–179 | year = 2001 | pmid = 11596125 | doi = 10.1002/glia.1106 }}</ref>
====Activated 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 [[necrosis]] factors, 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). In addition, the microglia also undergo rapid proliferation in order to increase their numbers for the upcoming battle. Activated non-phagocytic microglia generally appear as “bushy,” “rods,” or small ameboids depending on how far along the ramified to full phagocytic transformation gradient they are.<ref name= "Christensen 2006">{{cite journal | author = Christensen RN, Ha BK, Sun F, Bresnahan JC, Michael SB. | title = Kainate Induces Rapid Redistribution of the Actin Cytoskeleton in Ameboid Microglia | journal = Journal of Neuroscience Research | volume = 84 | pages = 170–181 | year = 2006 | pmid = 16625662 | doi = 10.1002/jnr.20865 }}</ref><ref name= "Aloisi 2001">{{cite journal | author = Aloisi F | title = Immune Function of Microglia | journal = Glia | volume = 36 | pages = 165–179 | year = 2001 | pmid = 11596125 | doi = 10.1002/glia.1106 }}</ref> <ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref>
====Activated 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 [[inflammatory]] 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.<ref name= "Aloisi 2001">{{cite journal | author = Aloisi F | title = Immune Function of Microglia | journal = Glia | volume = 36 | pages = 165–179 | year = 2001 | pmid = 11596125 | doi = 10.1002/glia.1106 }}</ref> <ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref>
====Gitter Cells (Compound Granular corpuscle):====
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.<ref name= "Rissi 2006">{{cite journal | author = Rissi DR, Oliveira FN, Rech RR, Pierezen F, Lemos RAA, Barros CSL | title = Epidemiology, clinical signs and distribution of the encephalic lesions in cattle affected by meningoencephalitis caused by bovine herpesvirus-5 | journal = Pesquisa Vetreinaria Brasileira | volume = 26 | issue= 2 | pages = 123–132 | year = 2006 }}</ref>
====Perivascular Microglia:====
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 lamina]]. 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.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref> These microglia have been shown to be essential to repair of [[Blood vessel|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.<ref name= "Ritter 2006">{{cite journal | author = Ritter MR, Banin E, Moreno SK, Aguilar E, Dorrel MI, Friedlander M | title = Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy | journal = Journal of Clinical Investination | volume = 116 | issue= 12 | pages = 3266–3276 | year = 2006 | pmid = 17111048 | doi = 10.1172/JCI29683 }}</ref>
====Juxtavascular:====
Like perivascular microglia, juxtavascular microglia can be distinguished mainly by their location. Juxtavascular microglia are found making direct contact with the [[basal lamina]] 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.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref>
==Normal Functions of Microglial Cells==
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. <ref name= "Aloisi 2001">{{cite journal | author = Aloisi F | title = Immune Function of Microglia | journal = Glia | volume = 36 | pages = 165–179 | year = 2001 | pmid = 11596125 | doi = 10.1002/glia.1106 }}</ref> 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 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]].<ref name= "Ferrer 1990">{{cite journal | author = Ferrer I, Bernet E, Soriano E, Del Rio T, Fonseca M | title = Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes | journal = Neuroscience | volume = 39 | pages = 451–458 | year = 1990 | pmid = 2087266 | doi = 10.1016/0306-4522(90)90281-8 }}</ref>
====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 [[viruses]], [[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]].
====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 H<sub>2</sub>O<sub>2</sub> and NO in a process known as ‘[[respiratory burst]]’. 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 [[Interleukin 1|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, viruses, 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.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref>
====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 INF-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.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref><ref name= "Aloisi 2001">{{cite journal | author = Aloisi F | title = Immune Function of Microglia | journal = Glia | volume = 36 | pages = 165–179 | year = 2001 | pmid = 11596125 | doi = 10.1002/glia.1106 }}</ref>
====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]].<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref>
====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.<ref name= "Gehrmann 1995">{{cite journal | author = Gehrmann J, Matsumoto Y, Kreutzberg GW | title = Microglia: intrinsic immuneffector cell of the brain | journal = Brain Research Reviews | volume = 20 | pages = 269–287 | year = 1995 | pmid = 7550361 | doi = 10.1016/0165-0173(94)00015-H }}</ref><ref name= "Ritter 2006">{{cite journal | author = Ritter MR, Banin E, Moreno SK, Aguilar E, Dorrel MI, Friedlander M | title = Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy | journal = Journal of Clinical Investination | volume = 116 | issue= 12 | pages = 3266–3276 | year = 2006 | pmid = 17111048 | doi = 10.1172/JCI29683 }}</ref>
====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]], [[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]]. [[Interleukin 8|IL-8]] promotes [[B-cell]] growth and differentiation, allowing it to assist microglia in fighting infection. Another [[cytokine]], [[Interleukin 1|IL-1]], inhibits the [[cytokines]] [[Interleukin 10|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, [[Interleukin 8|IL-8]], and MIP-3β. Finally, PGE<sub>2</sub> and other [[prostanoids]] help prevent [[chronic inflammation]] by inhibiting microglial pro-inflammatory response and downregulating [[Th1]] (T-helper cell) response.<ref name= "Aloisi 2001">{{cite journal | author = Aloisi F | title = Immune Function of Microglia | journal = Glia | volume = 36 | pages = 165–179 | year = 2001 | pmid = 11596125 | doi = 10.1002/glia.1106 }}</ref>
==Physiology of chronic neuroinflammation==
The word neuroinflammation has come to stand for chronic, [[central nervous system]] (CNS) specific, inflammation-like glial responses that may produce neurodegenerative symptoms such as [[senile plaques|plaque]] formation, dystrophic [[neurite]] growth, and excessive [[tau (protein)|tau]] phosphorylation.<ref name="Streita">{{cite journal | last=Streita |first=Wolfgang |date= 2006 | title= Microglial senescence: does the brain’s immune system have an expiration date? | journal= Trends in Neurosciences | volume= 29 |issue= 9 | pages= 506–510 | doi= 10.1016/j.tins.2006.07.001}}</ref> 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.<ref name="Streita"> </ref> 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.<ref name="Streita"> </ref>
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 [[mediator (coactivator)|mediators]]. These mediators are important in the normal functions of microglia and their production is usually decreased once their task is complete.<ref name="Wood">{{cite book | last= Wood | first= Paul | title= Neuroinflammation: Mechanisms and Management| publisher= Humana Press| date= 2003}}</ref> In chronic neuroinflammation, microglia remain activated for an extended period during which the production of mediators is sustained longer than usual.<ref name="Wood"> </ref> This increase in mediators contributes to neuronal death.<ref name="Wood"> </ref>
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.<ref name="Wood"> </ref> The following list contains a few of the numerous substances that are secreted when microglia are activated:
===Cytokines===
Microglia activate the proinflammatory [[cytokines]] [[interleukin 1|IL-1α]], [[interleukin 1|IL-1β]] and [[tumor necrosis factor-alpha|TNF-α]] in the CNS.<ref name="Wood"> </ref> Cytokines play a potential role in neurodegeneration when microglia remain in a sustained activated state.<ref name="Wood"> </ref> Direct injection of the cytokines IL-1α, IL-1β and TNF-α into the CNS result in local inflammatory responses and neuronal degradation.<ref name="Wood"> </ref> This is in contrast with the potential neurotrophic (inducing growth of neurons) actions of these cytokines during acute neuroinflammation.<ref name="Wood"> </ref>
===Chemokines===
[[Chemokines]] are cytokines that stimulate directional migration of inflammatory cells [[in vitro]] and [[in vivo]].<ref name="Wood"> </ref> Chemokines are divided into four main subfamilies: C, CC, CXC, and CX<sub>3</sub>C. Microglial cells are sources of some chemokines and express the monocyte chemoattractant protein-1 ([[MCP-1]]) chemokine in particular.<ref name="Wood"> </ref> 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. <ref name="Wood"> </ref> Microglia can express CCR3, [[CCR5]], CXCR4, and [[CX3CR1]] in vitro.<ref name="Wood"> </ref> Chemokines are proinflammatory and therefore contribute to the neuroinflammation process.<ref name="Wood"> </ref>
===Proteases===
When microglia are activated they induce the synthesis and secretion of [[proteolytic]] enzymes that are potentially involved in many functions.<ref name="Wood"> </ref> There are a number of [[proteases]] that possess the potential to degrade both the [[extracellular matrix]] and neuronal cells that are in the neighborhood of the microglia releasing these compounds.<ref name="Wood"> </ref> 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.<ref name="Wood"> </ref> 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).<ref name="Wood"> </ref> [[Elastase]], another protease, could have large negative effects on the extracellular matrix.<ref name="Wood"> </ref>
===Amyloid precursor protein===
Microglia synthesize [[amyloid precursor protein]] (APP) in response to [[Excitotoxicity|excitotoxic]] injury. <ref name="Wood"> </ref> [[senile plaques|Plaques]] result from abnormal [[proteolytic]] cleavage of membrane bound APP.<ref name="Wood"> </ref> Amyloid plaques can stimulate microglia to produce neurotoxic compounds such as cytokines, excitotoxin, nitrite oxide and lipophylic [[amines]], which all cause neural damage.<ref name="Golden">{{cite journal | last=Golden |first= Nyoman |coauthors= Sajid Darmadipura|date= 2007 | title= The Role of Microglia as Prime Component of CNS Immune System in Acute and Chronic Neuroinflammation| journal= Folica Medica Indonesiana| volume= 43| issue= 1| pages= 54–58}}</ref> Plaques in Alzheimer’s disease contain activated microglia.<ref name="Wood"> </ref> A study has shown that direct injection of amyloid into brain tissue activates microglia, which reduces the number of neurons.<ref name="Golden"> </ref> Microglia have also been suggested as a possible source of secreted β amyloid.<ref name="Wood"> </ref>
==Aging of microglia==
Microglia undergo a burst of [[mitotic]] activity during injury; this proliferation is followed by [[apoptosis]] to reduce the cell numbers back to baseline.<ref name="Streita"> </ref> 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.<ref name="Streita"> </ref> 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.<ref name="Streita"> </ref>
Accumulation of minor neuronal damage that occurs during normal aging can transform microglia into enlarged and activated cells.<ref name="Mrak"> {{cite journal | last=Mrak |first= Robert| coauthors= Sue Griffin | date= 2005| title= Glia and their cytokines in progression of neurodegeneration| journal= Neurobiology of Aging| volume= 26| pages= 349–354| doi= 10.1016/j.neurobiolaging.2004.05.010}}</ref> 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 and susceptible patients.<ref name="Mrak"> </ref> DNA damage might contribute to age-associated microglial activation. Another factor might be the accumulation of [[advanced glycation endproducts]], which accumulate with aging.<ref name="Mrak"> </ref> These proteins are strongly resistant to proteolytic processes and promote protein [[cross-linking]].<ref name="Mrak"> </ref>
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.”<ref name="Streita"> </ref> The incidence of dystrophic microglia increases with aging.<ref name="Streita"> </ref> Microglial degeneration and death have been reported in research on [[Transmissible spongiform encephalopathies|Prion disease]], [[Schizophrenia]] and Alzheimer’s disease, indicating that microglial deterioration might be involved in neurodegenerative diseases.<ref name="Streita"> </ref> A complication of this theory is the fact that it is difficult to distinguish between “activated” and “dystrophic” microglia in the human brain.<ref name="Streita"> </ref>
==Neurodegeneration==
[[Neurodegenerative]] disorders are characterized by progressive cell loss in specific neuronal populations.<ref name="Wood"> </ref> “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.”<ref name="Wood"> </ref> The following are prominent examples of microglial cells' role in neurodegenerative disorders.
===Alzheimer’s disease===
[[Alzheimer’s disease]] (AD) is a progressive, neurodegenerative disease where the brain develops abnormal clumps (amyloid plaques) and tangled fiber bundles ([[neurofibrillary tangles]]).<ref name="AlzWeb">{{ cite web| title= National Institute of Neurological Disorders and Stroke| date= Nov. 14th, 2007 | publisher= NINDS Alzheimer’s Disease Information Page |url= http://www.ninds.nih.gov/disorders/alzheimersdisease/alzheimersdisease.htm}}</ref>
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.<ref name="Mrak"> </ref> This over expression of IL-1 leads to excessive tau phosphorylation that is related to tangle development in Alzheimer’s disease.<ref name="Mrak"> </ref>
Many activated microglia are found to be associated with amyloid deposits in the brains of Alzheimer’s patients.<ref name="Wood"> </ref> Microglia interact with β-amyloid plaques through cell surface receptors that are linked to [[tyrosine kinase]] based signaling cascades that induce inflammation.<ref name="Wood"> </ref> 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.<ref name="Wood"> </ref>
====Treatment====
Non-steroidal anti-inflammatory drugs ([[NSAIDs]]) have proven to be effective in reducing the risk of AD.<ref name="Wood"> </ref> "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%."<ref name="Wood"> </ref>
===Parkinson’s disease===
[[Parkinson’s disease]] is a movement disorder in which the [[dopamine]] producing neurons in the brain, don’t work properly.<ref name="ParkWeb">{{cite web| publisher= National Institute of Neurological Disorders and Stroke| date= Nov 13th 2007| title= Parkinson’s Disease: Hope Through Research | url= http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm#90583159}}</ref> The area of the brain affected by Parkinson’s is called the [[substantia nigra]]. It is here that the neurons either become impaired or die.<ref name="ParkWeb"> </ref> The substantia nigra has one of the highest concentrations of microglia in the brain.<ref name="Wood"> </ref>
Activated microglial cells have been found around extraneuronal [[neuromelanin]] released from impaired dopaminergic neurons in the substantia nigra of patients with Parkinson’s disease.<ref name="Wilms"> {{ cite journal| last= Wilms | first= Henrik | coauthors= et al.| date= 2003| title= Activation of microglia by human neuromelanin is NF-kB dependent and involved p38 mitogen-activated protein kinase: implications for Parkinson’s Disease| journal= The FASEB Journal| volume= 17| pages= 500–502}}</ref> A study by Henrik Wilms discovered that neuromelanin acts as a chemoattractant for microglial cells and induces morphological transformation of microglia cells to an activated state.<ref name="Wilms"> </ref> Neuromelanin also induces synthesis of proinflammatory microglial molecules.<ref name="Wilms"> </ref> All of the inflammatory compounds that are up-regulated in Parkinson’s disease can be produced by microglia, especially activated microglia.<ref name="Wood"> </ref>
Another study conducted by Wei Zhang stated, “…We have shown for the first time aggregated [[alpha-synuclein|α-synuclein]], the major components of [[Lewy bodies]] in patients with Parkinson's disease or [[dementia with Lewy bodies]], activated microglia leading to enhanced dopaminergic neurotoxicity.”<ref name="Zhang"> {{ cite journal| last= Zhang| first= Wei| coauthors= et al.|date= 2005| title= Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease| journal= The FASEB Journal| volume= 19| pages= 533–542| doi= 10.1096/fj.04-2751com| pmid= 15791003}}</ref>
==Microglia and viruses==
===Human Immunodeficiency Virus (HIV)===
The infection of mononuclear phagocytes with [[HIV-1 protease|HIV-1]] is an important element in the development of [[HIV]]-associated dementia complex (HAD).<ref name="Rock"> {{ cite journal| last= Rock| first= Bryan| coauthors= et al | date= 2004| title= Role of Microglia in Central Nervous System Infections| journal= Clinical Microbiology Reviews| volume= 17| issue= 4|pages= 942–964| doi= 10.1128/CMR.17.4.942-964.2004| pmid= 15489356}}</ref> The only brain cell type that is “productively” infected with the virus are microglial cells. <ref name="Rock"> </ref>It has also become clear that neurotoxic mediators released from brain microglia play an important role in the pathogenesis of HIV-1.<ref name="Rock"> </ref>
“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.”<ref name="Rock"> </ref>
Infected microglia contain viral particles intracellularly.<ref name="Rock"> </ref> There is a correlation between the severity of dementia and microglial production of neurotoxins.<ref name="Rock"> </ref>
One discrepancy in HAD is the limited number of HIV-1 infected microglia in comparison to the many CNS abnormalities that occur.<ref name="Rock"> </ref> 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.”<ref name="Rock"> </ref>
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).<ref name="Rock"> </ref>
===Herpes simplex virus===
[[Herpes simplex virus]] (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.<ref name="Rock"> </ref> Microglia produce cytokines that are toxic to neurons; this may be a mechanism underlying HSV-related CNS damage.<ref name="Rock"> </ref> It has been found that “active microglial cells in HSV encephalitis patients do persist for more than 12 months after antiviral treatment.”<ref name="Rock"> </ref>
==Microglia and bacteria==
[[Lipopolysaccharide]] (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]].<ref name="Rock"> </ref> “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.”<ref name="Rock"> </ref>
===Streptococcus pneumoniae===
[[Streptococcus pneumoniae]] 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]].<ref name="Rock"> </ref> Microglia interact with streptococcus via their TLR2 receptor; this interaction then activates microglia to produce nitric oxide which is neurotoxic. <ref name="Seija"> {{cite journal | last=Lehnardt | first = Seija | coauthor = et al. | title = TLR2 and Caspase-8 Are Essential for Group B Streptococcus-Induced Apoptosis in Microglia | journal= J Immunol. | date= 2007 | volume= 179 | issue = 9 | pages=6134–6143}}</ref> The inflammatory response, triggered by microglia, may cause intracerebral [[edema]].<ref name="Rock"> </ref>
==Microglia and parasites==
===Plasmodium falciparum===
[[Plasmodium falciparum]] is a [[parasite]] that causes [[malaria]] in humans.<ref name="Rock"> </ref> A serious complication of malaria is cerebral malaria (CM).<ref name="Rock"> </ref> CM occurs when red blood cells break through the blood brain barrier causing microhemorrhages, [[ischemia]] and glial cell growth.<ref name="Rock"> </ref> This can lead to microglial aggregates called Durck’s [[granulomas]].<ref name="Rock"> </ref> Recent research has indicated that microglia play a major role in the pathogenesis of CM.<ref name="Rock"> </ref>
==Current attempts to control neuroinflammation==
===Inhibit microglia 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]]).<ref name="Wood"> </ref> Previous approaches to down-regulate activated microglia focused on [[immunosuppressants]].<ref name="Wood"> </ref> Recently, [[minocycline]] (a [[tetracycline]] derivative) has shown down-regulation of microglial MAPK.<ref name="Wood"> </ref> Another promising treatment is CPI-1189, which induces cell death in a [[TNF]] α-inhibiting compound that also down-regulates MAPK.<ref name="Wood"> </ref>
===Regulate chemokine receptor===
The chemokine receptor, [[CX3CR1]], is expressed by microglia in the central nervous system.<ref name="Cardona"> {{ cite journal| last= Cardona| first= Astrid |coauthors= et al.| date= 2006| title= Control of microglial neurotoxicity by the fractalkine receptor| journal= Nature Neuroscience| volume= 9 | issue= 7| pages= 917–924| doi= 10.1038/nn1715}}
</ref> [[Fractalkine]] (CX3CL1) is the exclusive ligand for CX3CR1 and is made as a transmembrane [[glycoprotein]] from which a chemokine can be released.<ref name="Cardona"> </ref> Cardona, et al. stated in 2006 that “using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity.”<ref name="Cardona"> </ref> Further studies into how CX3CR1 regulates microglial [[neurotoxicity]] could lead to new therapeutic strategies for neuroprotection.<ref name="Cardona"> </ref>
===Inhibit amyloid deposition===
Inhibitors of amyloid deposition include the enzymes responsible for the production of extracellular amyloid such as [[beta-secretase|β-secretase]] and [[gamma-secretase|γ-secretase]] inhibitors.<ref name="Wood"> </ref> 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.<ref name="Wood"> </ref> Another strategy involves increasing the antibodies against a fragment of amyloid.<ref name="Wood"> </ref> This treatment is also in phase II clinical trials for the treatment of Alzheimer’s disease.<ref name="Wood"> </ref>
===Inhibit cytokine synthesis===
[[Glucocorticosteroids]] (GCS) are anti-inflammatory steroids that inhibit both central and peripheral cytokine synthesis and action.<ref name="Wood"> </ref> In a study conducted by Kalipada Pahan from the Department of Pediatrics at the Medical University of South Carolina, both [[lovastatin]] and [[sodium phenylacetate]] were found to inhibit TNF-α, IL-1β, and IL-6 in rat microglia.<ref name="Pahan"> {{cite journal | last= Pahan | first=Kalipada | coauthor= et al. | title= Lovastatin and Phenylacetate Inhibit the Induction of Nitric Oxide Synthase and Cytokines in Rate Primary Astrocytes, Microglia, and Macrophages | journal= J. Clin. Invest. | volume= 100 | issue= 11 | date = 1997 | pages= 2671–2679 | doi= 10.1172/JCI119812}}</ref> 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.<ref name="Pahan"> </ref>
==References==
{{reflist}}
==External links==
*[http://www.microglia.net/microglia.htm Microglia home page] at microglia.net
*[http://cmr.asm.org/cgi/content/full/17/4/942 The Role of Microglia in the Central Nervous System] - Clinical Microbiology Reviews October 2004, p. 942-964, Vol. 17, No. 4
*[http://www.scq.ubc.ca/?p=674 Creeping into your Head - A Brief Introduction to Microglia] - A Review from the Science Creative Quarterly
* {{cite web |url=http://focus.hms.harvard.edu/2007/040607/neuroscience.shtml |title=Immune Scavengers Target Alzheimer’s Plaques | April 6, 2007 | NEUROSCIENCE: Immune Scavengers Target Alzheimer’s Plaques |accessdate=2007-05-09 |format= |work=}} - from [[Harvard University]]
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{{Nervous tissue}}
[[Category:Nervous system]]
[[Category:Macrophages]]
[[Category:Glial cells]]
[[Category:Human cells]]
[[fa:میکروگلیال]]
[[id:Mikroglia]]
[[he:מיקרוגליה]]
[[ja:小膠細胞]]
[[pl:Mikroglej]]
[[pt:Micróglia]]
[[ru:Микроглия]]
[[tr:Mikrogliya]]