Instruct: Given a question, retrieve documents that answer the question.
Query: How was microglia discovered?
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 Victor Babeş while studying a rabies case in 1897. Babeş noted the cells were found in a variety of viral brain infections but did not know what the clusters of microglia he saw were.[30] 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."[31][32] 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.
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.[8] 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.[24]
Gliotransmission can also occur between two types of glial cells: astrocytes and microglia. Calcium waves within the intracellular matrix of the astrocyte can cause a response in microglia with the presence of ATP in the extracellular matrix. One study demonstrated that a mechanical stimulation caused astrocytes to release ATP, which in turn caused a delayed calcium response in microglia, suggesting that astrocyte-to-microglia communication could be mediated by ATP.
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.
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.[27]
Oligodendrocytes fail to recruit macrophages for debris removal. Macrophage entry in general into CNS site of injury is very slow. In contrast to PNS, Microglia play a vital role in CNS wallerian degeneration. However, their recruitment is slower in comparison to macrophage recruitment in PNS by approximately 3 days. Further, microglia might be activated but hypertrophy, and fail to transform into fully phagocytic cells. Those microglia that do transform, clear out the debris effectively. Differentiating phagocytic microglia can be accomplished by testing for expression of Major histocompatibility complex (MHC) class I and II during wallerian degeneration.[18] The rate of clearance is very slow among microglia in comparison to macrophages. Possible source for variations in clearance rates could include lack of opsonin activity around microglia, and the lack of increased permeability in the blood–brain barrier. The decreased permeability could further hinder macrophage infiltration to the site of injury.[10]
Microglia undergo a burst of mitotic activity during injury; this proliferation is followed by apoptosis to reduce the cell numbers back to baseline.[28] 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.[28] 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.[28]
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."[8][17][22]
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.[10]
In 2012, Stevens’s team published evidence that microglia 'eat' synapses, especially those that are weak and unused. The findings pinned down a new role for microglia in wiring the brain, indicating that adult neural circuitry is determined not only by nerve cells but also by the brain’s immune cells; this helped to explain how the brain, which starts out with a surplus of neurons, trims some of the excess away. Neuron named the paper its most influential publication of 2012.
"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. Microglia interact with streptococcus via their TLR2 receptor; this interaction then activates microglia to produce nitric oxide which is neurotoxic. The inflammatory response, triggered by microglia, may cause intracerebral edema.
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."[28] The incidence of dystrophic microglia increases with aging.[28] Microglial degeneration and death have been reported in research on Prion disease, Schizophrenia and Alzheimer's disease, indicating that microglial deterioration might be involved in neurodegenerative diseases.[28] A complication of this theory is the fact that it is difficult to distinguish between "activated" and "dystrophic" microglia in the human brain.[28]
The fourth proposed major mechanism of neuronal death in Parkinson's Disease, neuroinflammation, is generally understood for neurodegenerative diseases, however, specific mechanisms are not completely characterized for PD. One major cell type involved in neuroinflammation is the microglia. Microglia are recognized as the innate immune cells of the central nervous system. Microglia actively survey their environment and change their cell morphology significantly in response to neural injury. Acute inflammation in the brain is typically characterized by rapid activation of microglia. During this period, there is no peripheral immune response. Over time, however, chronic inflammation causes the degradation of tissue and of the blood–brain barrier. During this time, microglia generate reactive oxygen species and release signals to recruit peripheral immune cells for an inflammatory response.
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.
AIF1 is a protein that exists in the cytoplasm, and it is highly evolutionarily conserved. It is also possibly identical to three other proteins, Iba-2, MRF-1 (microglia response factor) and daintain. However complete functional profiles of all three proteins and how they overlap is unknown. IBA1 is a 17-kDa EF hand protein that is specifically expressed in macrophages / microglia and is upregulated during the activation of these cells. Iba1 expression is up-regulated in microglia following nerve injury, central nervous system ischemia, and several other brain diseases.
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.
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.[8]
Although historically frequently used, the term "activated" microglia should be replaced by "reactive" microglia.[19] 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.[20]
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 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.[16]
Georg Kreutzberg researched as experimental neuropathologist on the cellular mechanisms of brain and nerve disorders, especially on regeneration and repair mechanisms in the brain as well as the role of glia cells in brain diseases. He was regarded as a leader in the investigation of microglia cells - the crucial defense cells of brain tissue. He discovered the blocking effect of colchicine on axonal and dendritic transport in nerve cells. Using the experimental model provided by the facial motor nucleus following axotomy Kreutzberg and his fellow workers discovered essential parameters of the regeneration program of nerve cells. Here, he developed also the activation concept of microglia cells, which revealed new directions for the understanding of many brain diseases.
The chemokine receptor, CX3CR1, is expressed by microglia in the central nervous system. Fractalkine (CX3CL1) is the exclusive ligand for CX3CR1 and is made as a transmembrane glycoprotein from which a chemokine can be released. Cardona, et al. stated in 2006 that "using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity." Further studies into how CX3CR1 regulates microglial neurotoxicity could lead to new therapeutic strategies for neuroprotection.
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.[8][16]
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.
Microglia are a collective type of neuroglia (glial cell) located throughout the brain and spinal cord.[1], as of 2018 found to have 9 distinct subtypes with different functions, appearance, and presence[2][3]. Microglia account for 10–15% of all cells found within the brain.[4] As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS).[5] Microglia (and other neuroglia including astrocytes) are distributed in large non-overlapping regions throughout the CNS.[6][7] 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.[8] Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS.[9] This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium.[8]
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.[8][16][17][21]