Microglia represent the endogenous brain defence and immune system, which is responsible for CNS protection against various types of pathogenic factors. Microglial cells derive from progenitors that have migrated from the periphery and are from mesodermal/ mesenchymal origin. During postnatal development they immigrate into the brain commonly until postnatal day 10 in rodents. After invading the CNS, microglial precursors disseminate relatively homogeneously throughout the neural tissue and acquire a specific phenotype, which clearly distinguish them from their precursors, the blood-derived monocytes.
The ´resting´ microglia are the fastest moving cells in the brain
Under physiological conditions microglia in the CNS exist in the ramified or what was generally termed the ‘resting’ state. The resting microglial cell is characterized by a small cell body and much elaborated thin processes, which send multiple branches and extend in all directions. Similar to astrocytes, every microglial cell has its own territory, about 15 - 30 µm wide; there is very little overlap between neighbouring territories. The processes of resting microglial cells are constantly moving through its territory; this is a relatively rapid movement with a speed of about 1.5 µm/min and thus microglial processes represent the fastest moving structures in the brain. At the same time microglial processes also constantly send out and retract small protrusions, which can grow and shrink by 2–3 µm/min. The microglia seem to be randomly scanning through their domains. Recent studies, however, have demonstrated that these processes rest for periods of minutes at sites of synaptic contacts. Considering the velocity of this movement, the brain parenchyma can be completely scanned by microglial processes every several hours. The motility of the processes is not affected by neuronal firing, but it is sensitive to activators (ATP and its analogues) and inhibitors of purinoceptors. Focal neuronal damage induces a rapid and concerted movement of many microglial processes towards the site of lesion, and within less than an hour the latter can be completely surrounded by these processes. This injury-induced motility is also governed, at least in part, by activation of purinoceptors; it is also sensitive to the inhibition of gap junctions, which are present in astrocytes, but not in microglia; inhibition of gap junctions also affects physiological motility of astroglial processes. Therefore, it appears that astrocytes signal to the microglia by releasing ATP (and possibly some other molecules) through connexin hemichannels. All in all, microglial processes act as a very sophisticated and fast scanning system. This system can, by virtue of receptors residing in the microglial cell plasmalemma, immediately detect injury and initiate the process of active response, which eventually triggers the full blown microglial activation.
Activation of microglia
When a brain insult is detected by microglial cells, they launch a specific program that results in the gradual transformation of resting, ramified microglia into an ameboid form; this process is generally referred to as ‘microglial activation’ and proceeds through several steps. During the first stage of microglial activation resting microglia retract their processes, which become fewer and much thicker, increase the size of their cell bodies, change the expression of various enzymes and receptors, and begin to produce immune response molecules. Some microglial cells return into a proliferative mode, and microglial numbers around the lesion site start to multiply. Microglial cells become motile, and using amoeboid-like movements they gather around sites of insult. If the damage persists and CNS cells begin to die, microglial cells undergo further transformation and become phagocytes. This is, naturally, a rather sketchy account of the complex and highly coordinated changes which occur in microglial cells; the process of activation is gradual and most likely many sub-states exist on the way from resting to phagocytic microglia. Furthermore, activated microglial cells may display quite heterogeneous properties in different types of pathologies and in different parts of the brain.
The precise nature of the initial signal that triggers the process of microglial activation is not fully understood; it may be associated either with withdrawal of some molecules (the ‘off-signal’) released during normal CNS activity, or by the appearance of abnormal molecules or abnormal concentrations of otherwise physiologically present molecules (on-signal). Both types of signalling can provide microglia with relevant information about the status of brain parenchyma within their territorial domain.
The ‘off-signals’ that may indicate deterioration in neural networks are not yet fully characterized. A good example for this type of communication are neurotransmitters. Microglial cells express a variety of the classical neurotransmitter receptors such as receptors for GABA, glutamate, dopamine, noradreanline. In most cases, activation of the receptors counteracts the activation of microglial cells with respect to acquiring a pro-inflammatory phenotype. One might speculate that depression of neuronal activity could affect neighbouring microglia, turning them into an ‘alerted’ state. In fact these ‘off-signals’ allow microglia to sense disturbance even if the nature of the damaging factor cannot be identified.
The ‘on-signalling’ is conveyed by a wide array of molecules, either associated with cell damage or with foreign matter invading the brain. In particular, damaged neurones can release high amounts of ATP, cytokines, neuropeptides, growth factors. Many of these factors can be sensed by microglia and trigger activation. It might well be that different molecules can activate various subprogrammes of this routine, regulating therefore the speed and degree of microglial activation. Some of these molecules can carry both ‘off’ and ‘on’ signals: for example low concentrations of ATP may be indicative of normal on-going synaptic activity, whereas high concentrations signal cell damage. Microglia are also capable of sensing disturbances in brain metabolism: for example, accumulation of ammonia, which follows grave metabolic failures (e.g. during hepatic encephalopathy) can activate microglial cells either directly or via intermediates such as NO or ATP.
Migration and motility
Microglial migration is essential for many pathophysiological processes, including immune defence and wound healing. Microglial cells exhibit two types of movement activity: in the ramified (“resting”) form, they actively move their processes without translocation of the cell body as was already described above. In the amoeboid form, microglial cells not only move their processes, but in addition the entire cell can migrate through the brain tissue. Microglial migration occurs in development, when invading monocytes disseminate through the brain. Another type of migration is triggered by a pathologic insult when ramified microglia undergoes activation, transform into the amoeboid form and migrate to the site of injury. There are many candidate molecules which may serve as pathological signals and initiate microglial migration and act as chemoattractant molecules. These molecules include ATP, cannabinoids, chemokines, lysophosphatidic acid and bradykinin. The actual movement of microglial cells involves redistribution of salt and water and various ion channels and transporters important for this process. In particular, K+ channels, Cl- channels, Na+/H+ exchanger, Cl-/HCO3- exchanger, and Na+/HCO3- cotransporter contribute to microglial motility and migration.
Microglial cells are the professional innate phagocytes of the CNS tissue. This function is important for the normal brain, during brain development, and in pathology and regeneration. In the CNS development microglial phagocytosis is instrumental in removing apoptotic cells and may be involved in synapse removal during development and potentially in pruning synapses in the postnatal brain. Microglial phagocytosis is intimately involved in many neurological diseases. In response to the lesion, microglial cells accumulate at the damaged site and remove cellular debris or even parts of damaged cells. Through phagocytosis microglial cells can also accumulate various pathological factors such as for example beta-amyloid in Alzheimer’s disease or myelin fragments in demyelinating diseases. Multiple factors, receptors and signalling cascades can regulate the phagocytic activity. In particular microglial phagocytosis is controlled by purinoceptors; the metabotropic P2Y6 receptors stimulate whereas ionotropic P2X7 receptors inhibit phagocytotic activity. Microglial phagocytosis is also controlled by glial derived neurotrophic factor, by ciliary neurotrophic factor, by TOLL receptors, by prostanoid receptor etc.
Microglial cells are the dominant antigen presenting cells in the central nervous system. Under resting conditions the expression of the molecular complex for presenting antigen, the major histocompatibility complex II (MHCII) and co-stimulatory molecules such as CD80, CD86 and CD40 is below detection. Upon injury the molecules are highly upregulated and the expression of this complex is essential for interacting with T lymphocytes. This upregulation has been described in a number of pathologies and is well studied in Multiple Sclerosis. Microglial cells phagocytose myelin, degrade it and present peptides of the myelin proteins as antigens. By releasing cytokines such as CCl2 microglial cells are important for recruiting leucocytes into the CNS. Microglia interact with infiltrating T lymphocytes and, thus, mediate the immune response in the brain. They have the capacity to stimulate proliferation of both TH1- and TH2-CD4 positive T cells.
Adapted from: Kettenmann H.; Verkhratsky A. (2011) Neuroglia - Living Nerve Glue, Fortschritte der Neurologie und Psychiatrie 79: 588-597