Microglial cell

Microglia are a type of neuroglia (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 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. Microglia are a type of neuroglia (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 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. 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. 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. The microglial sensome is a relatively new biological concept that appears to be playing a large role in neurodevelopment and neurodegeneration. The sensome refers to the unique grouping of protein transcripts used for sensing ligands and microbes. In other words, the sensome represents the genes required for the proteins used to sense molecules within the body. The sensome can be analyzed with a variety of methods including qPCR, RNA-seq, microarray analysis, and direct RNA sequencing. Genes included in the sensome code for receptors and transmembrane proteins on the plasma membrane that are more highly expressed in microglia compared to neurons. It does not include secreted proteins or transmembrane proteins specific to membrane bound organelles, such as the nucleus, mitochondria, and endoplasmic reticulum. The plurality of identified sensome genes code for pattern recognition receptors, however, there are a large variety of included genes. Microglial share a similar sensome to other macrophages, however they contain 22 unique genes, 16 of which are used for interaction with endogenous ligands. These differences create a unique microglial biomarker that includes over 40 genes including P2ry12 and HEXB. DAP12 appears to play an important role in sensome protein interaction, acting as a signalling adaptor and a regulatory protein. The regulation of genes within the sensome must be able to change in order to respond to potential harm. Microglia can take on the role of neuroprotection or neurotoxicity in order to face these dangers. For these reasons, it is suspected that the sensome may be playing a role in neurodegeneration. Sensome genes that are upregulated with aging are mostly involved in sensing infectious microbial ligands while those that are downregulated are mostly involved in sensing endogenous ligands. This analysis suggests a glial-specific regulation favoring neuroprotection in natural neurodegeneration. This is in contrast to the shift towards neurotoxicity seen in neurodegenerative diseases. The sensome can also play a role in neurodevelopment. Early-life brain infection results in microglia that are hypersensitive to later immune stimuli. When exposed to infection, there is an upregulation of sensome genes involved in neuroinflammation and a downregulation of genes that are involved with neuroplasticity. The sensome’s ability to alter neurodevelopment may however be able to combat disease. The deletion of CX3CL1, a highly expressed sensome gene, in rodent models of Rett syndrome resulted in improved health and longer lifespan. The downregulation of Cx3cr1 in humans without Rett syndrome is associated with symptoms similar to schizophrenia. This suggests that the sensome not only plays a role in various developmental disorders, but also requires tight regulation in order to maintain a disease-free state. 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. The marker Iba1, which is upregulated in reactive microglia, is often used to visualize these cells.