Microglia, also known as Microgliocytes, Gitter cells, or Hortega Cells, are a type of glial cell located throughout the brain and spinal cord. Microglia account for 10–15% of all cells found within the brain.
As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia (and other glia including astrocytes) are distributed in large non-overlapping regions throughout the CNS.
Microglia are key cells in overall brain maintenance — they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium.
The brain and spinal cord, which make up the central nervous system, 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 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.
Microglial cells fulfill a variety of different tasks within the CNS mainly related to both immune response and maintaining homeostasis.
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, neurofibrillary 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 regulating numbers of neural precursor cells and removing apoptotic neurons.
They also engulf synapses to regulate synaptic numbers. 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.
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.
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.
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 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.
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 hydrogen peroxide and nitric oxide 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 IL-1 promote demyelination of neuronal axons.
Finally, microglia can injure neurons through NMDA receptor-mediated processes by secreting glutamate, 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.
Role In 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 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 alter their gene expression. Altered 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 distinct from inflammation in other organs, but does include some similar mechanisms such as the localized production of chemo-attractant molecules to the site of inflammation.
The following list contains a few of the numerous substances that are secreted when microglia are activated:
Microglia activate the proinflammatory cytokines IFN-γ, IL-1α, IL-1β and TNF-α in the CNS. Direct injection of the cytokines IL-1α, IL-1β and TNF-α into the CNS result in local inflammatory responses and neuronal degradation.
Cytokines play a potential role in neurodegeneration when microglia remain in a sustained activated state. This is in contrast with the potential neurotrophic (inducing growth of neurons) actions of these cytokines during acute neuroinflammation.
Chemokines are cytokines that stimulate directional migration of inflammatory cells in vitro 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, CXCL8, CXCR4, and CX3CR1 in vitro. Chemokines are proinflammatory and therefore contribute to the neuroinflammation process.
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 matrix 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.
Amyloid Precursor Protein
Microglia synthesize amyloid precursor protein (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, nitric oxide and lipophylic amines, 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.
Role In Neurodegeneration
Microglia also have a role in neurodegenerative disorders, which 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.
There are many activated microglia over-expressing IL-1 in the brains of Alzheimer patients that are distributed with both Aβ 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.
One preliminary model as to how this would occur involves a positive feedback loop. When activated, microglia will secrete proteases, cytokines, and reactive oxygen species. The cytokines may induce neighboring cells to synthesize amyloid precursor protein.
The proteases then possibly could cause the cleaving required to turn precursor molecules into the beta amyloid that characterizes the disease. Then, the oxygen species encourage the aggregation of beta amyloid in order to form plaques. The growing size of these plaques then in turn triggers the action of even more microglia, which then secrete more cytokines, proteases, and oxygen species, thus amplifying the neurodegeneration.
Parkinson’s disease is a movement disorder in which the dopamine producing neurons in the brain do not function as they should; the neurons of the substantia nigra become dysfunctional and eventually die, leaving a lack of dopamine input into the striatum.
Glial cell line-derived neurotrophic factor (GDNF) may have the ability to chemoprotect the cells of the substantia nigra.
Role In Neuropathic Pain
Microglia have been implicated in neuropathic pain. They become activated in response to nerve injury, as demonstrated by several animal models. Activated microglia release substances that excite pain-sensitive neurons, including prostaglandins and reactive oxygen species, through the purinergic signaling mechanisms.
Moreover, microglia also release of proinflammatory molecules through the stimulation of purinergic receptors, including IL1-β, IL-6, and TNF-α. The release of these molecules is mediated by the P2X7 receptor and creates a positive feedback loop, exacerbating the pain response.
A causal role for microglia in the pathogenesis of neuropathic pain has been demonstrated through P2X4 receptor. P2X4 receptors are upregulated following injury and the increase in purinergic signaling activates p38-mitogen-activated protein kinase (p38 MAPK). The increase in p38 MAPK signaling leads to greater microglial release of brain-derived neurotrophic factor (BDNF). BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.
Therapeutic development has focused on finding purinergic signaling blockers. There has been some success with P2X7 blockers, A-438079 and A-740003, however there are no selective P2X4 receptor antagonists to date.
Forms Of Microglia
Microglial cells are extremely plastic, 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.
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.
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.
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.
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, 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.
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.
This shape allows the microglial 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.”
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. 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.
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Top Image: Rat microglia grown in tissue culture in green, along with nerve fiber processes shown in red. Credit: GerryShaw, CC BY-SA 3.0
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