microglia microglia microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. microglia account for about 10-15% of 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 neuroglia 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. recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed. microgliamicroglia in resting state from rat cortex before traumatic brain injury (lectin staining with hrp)microglia/macrophage – activated form from rat cortex after traumatic brain injury (lectin staining with hrp)detailsprecursorprimitive yolk-sac derived macrophagesystemcentral nervous systemidentifiersmeshd017628thh2.00.06.2.00004, h2.00.06.2.01025 fma54539anatomical terms of microanatomy 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 viral 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. forms rat microglia grown in tissue culture in green, along with nerve fiber processes shown in red. microglia in rat cerebellar molecular layer in red, stained with antibody to iba1/aif1. bergmann glia processes are shown in green, dna in blue. microglial cells are extremely 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. 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. 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. 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 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." gitter cells gitter cells are the eventual result of microglial cells' phagocytosis of infectious material or cellular debris. eventually, after engulfing a certain amount of material, the phagocytic microglial cell becomes unable to phagocytose any further materials. the resulting cellular mass is known as a granular corpuscle, named for its ‘grainy' appearance. by looking at tissue stained to reveal gitter cells, pathologists can visualize healed areas post-infection. perivascular unlike the other types of microglia mentioned above, "perivascular" microglia refers to the location of the cell, rather than its form/function. perivascular microglia are mainly found encased within the walls of the 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 their environment. perivascular microglia also react strongly to macrophage differentiation antigens. these microglia have been shown to be essential for the 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 these processes, myeloid recruitment and differentiation into microglial cells is highly accelerated to accomplish these tasks. 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. functions activation of microglia via purinergic signalling microglial cells fulfill a variety of different tasks within the cns mainly related to both immune response and maintaining homeostasis. the following are some of the major known functions carried out by these cells. 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, 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. there is also evidence that microglia can refine synaptic circuitry by engulfing and eliminating synapses. 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. 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, 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. antigen presentation as mentioned above, resident non-activated microglia act as poor antigen presenting