Microglia
Microglia also Hortega cells are multifunctional glial cells in the parenchyma of the central nervous system (CNS) and are counted among the tissue macrophages . They are not based on precursors from the bone marrow, but on yolk sac cells and make up about 10–15 percent of glial cells. As a link between the nervous and immune systems, they scan their surroundings in the intact brain and eliminate waste materials and cell debris through phagocytosis and pinocytosis . By breaking down or strengthening synapses, they contribute to neuronal plasticity . In the infected or injured brain, they contain damage, fight pathogens, attract additional immune cells and present them with antigens. While they have anti-inflammatory effects in acute disorders, they can contribute to chronic inflammation in longer-lasting disorders.
Origin and development
In contrast to almost all other vertebrate cells, microglia are all derived from progenitors from the yolk sac . So they are not based on hematopoietic stem cells in the bone marrow like other immune cells, with the exception of some tissue macrophages .
In mice, the first amoeboid precursor cells migrate from the yolk sac into the developing CNS from about the 7th day of embryonic development, first via blood vessels, then creeping, as there are no veins in the neuroepithelium. They are the first glial cells in the future brain; Astrocytes and oligodendrocytes only form later from the neuroectoderm. In humans, the yolk sac cells colonize the CNS in weeks 4-5 of gestation; a second wave of immigration at 12–13 weeks of gestation is restricted to white matter . After their settlement, the microglia change their shape; they form numerous branched runners. They also multiply massively after birth.
It is true that monocytes from the bone marrow can migrate into the brain and develop into macrophages there. But that happens mainly in the case of inflammation, and these macrophages do not settle permanently, but rather perish after the event or migrate back into the bloodstream.
Shape and equipment
Shortly after birth, microglia are still amoeboid; in the following weeks they branch out more and more.
In the resting state, mature microglia differ significantly from macrophages: the relatively small, stationary cell body has numerous richly branched and highly dynamic offshoots that scan the environment and make contact with neurons and other glial cells (oligodendrocytes and astrocytes).
When activated, the cell body thickens, the runners become shorter and are less branched. To remove distant objects through phagocytosis, the cells take on an amoeboid shape, in which a single thick ridge extends in the direction of the object and the rest of the cell may follow suit.
Mature microglia carry numerous receptors , the ligands of which are predominantly located on the axons and dendrites of neurons or are excreted by them. These include cytokines such as TGF-β , chemokines such as CX3CL1 (fractalkine), nucleotides such as adenosine triphosphate (ATP), hormones and neurotransmitters . In turn, microglia can secrete cytokines and the growth factors IGF1 and BDNF in order to influence the cells in their environment and to chemotactically attract immune cells from the blood vessels and the meninges. They also express MHC class I and class II complexes on which they can present antigens.
Protein production changes with the degree of activation of the microglia and the phase of life: In diseases or chronic stress and in old age, microglia release more inflammatory cytokines and form fewer receptors for the neuronal chemokine CX3CL1, which has a deactivating effect on them. During prenatal and postnatal development of the brain and in the intact adult brain, microglia produce high levels of CX3CL1 receptor and phagocytic proteins. At the same time, they only produce a few MHC class I and class II complexes, costimulators and integrins . Whether microglia have an inflammatory effect like classically activated macrophages or an anti-inflammatory effect like alternatively activated macrophages, depends on the age and condition of the CNS.
Function during the development of the brain
During the embryonic and child development of the brain, around half of all immature neurons die in a controlled manner, for example because they cannot form functional synapses. This apoptosis is triggered either by themselves or by neighboring microglia, for example through the release of reactive oxygen species . They then remove the microglia by phagocytosis so that the cell debris does not trigger inflammation. In this phase, the microglia multiply strongly and gather - chemotactically attracted by the dying neurons - in regions of the brain in which many remains have to be removed.
Microglia can also support prenatal and postnatal neurogenesis and the survival of neurons and oligodendrocytes through the growth factor IGF1. Before and after birth, they take part in synaptic pruning , i.e. the breakdown of rarely used synapses, and thus stabilize the signal transmission via the remaining synapses. Mediated by CX3CL1 and proteins of the complement system , the foothills of the microglia envelop presynaptic endings and dendritic thorns and break them down. Without this pruning of surplus synapses, different cognitive impairments (memory, motor skills, fear behavior etc.) occur depending on the affected brain region.
With their selective support and elimination of synapses, microglia also contribute to neural plasticity because they respond to changes in neural signal transmission. In the visual cortex of young mice that spend a few days in permanent darkness, they break down the synapses that are no longer needed by phagocytosis. The process is reversible: after returning to normal lighting conditions, new synapses are created in the visual cortex of the test animals.
Function in the intact brain
Even in the adult brain, microglia with numerous extensions constantly scan their surroundings. They respond to signals on the surfaces of neurons and glial cells as well as in the tissue fluid, such as ATP, by either stabilizing or breaking down synapses. The foothills are among the most dynamic cell structures in the body; they grow or shrink at around 1.5 micrometers per minute and absorb a lot of fluid through pinocytosis. This constant activity consumes a lot of energy, but maintains homeostasis in the CNS and enables rapid reactions to disorders such as injuries.
In the thalamus , cortex and hippocampus , microglia support neuronal plasticity even in adults and thus enable learning and adaptation to environmental conditions. Their foothills check a synapse about once an hour for about five minutes. Mediated by TGF-β and the complement proteins C1q and C3, they break down defective or unnecessary synapses.
The microglia continue to support neurogenesis in regions of the brain where there are still neural stem cells in adults. They also contribute to the immune privilege of the brain by secreting anti-inflammatory signaling substances, dampening Th1 responses from immune cells and causing the repair of damaged nerve tissue.
Despite the blood-brain barrier , microglia are in exchange with the periphery, for example via cytokines or short-chain fatty acids that are transported from the blood to the brain. In animal experiments, for example, intestinal bacteria and parasites influence the level of activity of the microglia in the brain.
Function in case of sterile injuries
In the case of a sterile injury to the CNS, the microglia are activated focally: they retract their runners and assume an amoeboid shape, crawl into the affected region if necessary and stretch out a long and wide ridge in the direction of the injury. They eliminate dying cells and leaked cell components through phagocytosis. This behavior is triggered, among other things, by nucleotides such as ATP and UDP from the injured cells.
After ischemia or an ischemic stroke , the usual control contacts between microglia and synapses last longer. Synapses that have been damaged by the lack of oxygen are broken down.
After compression of the meninges, honeycomb microglia envelop individual astrocytes in the glia limitans and thus help to strengthen this barrier between the meninges and the brain parenchyma. Dead astrocytes and other cells in the barrier are phagocytosed to eliminate.
Function in infections
After an infection, microglia ensure a quick first defense reaction. With their Pattern Recognition Receptors (PRRs) they register pathogens. When activated, they multiply, take on an amoeboid form and migrate to the site of infection. Depending on the location, they release pro-inflammatory or anti-inflammatory cytokines, chemokines, growth factors, complement proteins, nitric oxide , matrix metalloproteases (MMP) and reactive oxygen species. In doing so, they curb the spread of the pathogens and attract additional immune cells. They can present T lymphocyte antigens on their MHC class I and II complexes and thus activate the antigen-specific acquired defense. This eliminates most pathogens, but can also damage the surrounding CNS tissue.
Activated microglia are morphologically and functionally difficult to distinguish from macrophages, which arise in infections from immigrated monocytes and support the microglia.
Parasites
Protozoa such as Toxoplasma gondii , trypanosomes or plasmodia can often not be completely eliminated by the immune system because of their size. Instead, it locks them in cysts. In order to contain an infection with T. gondii , microglia activated by interferon-γ also release interferon-γ and they cooperate with other immune cells. For example, they attract cytotoxic CD8 + T lymphocytes with the chemokine CXCL10.
A chronic infection with T. gondii does not normally trigger neurodegeneration , as the microglia hardly present any antigens under the influence of the pathogen and dampen the immune response by releasing the anti-inflammatory cytokines TGF-β and interleukin-10 : Instead of severe brain damage, a persistently vigorous defense reaction Risking, the brain will tolerate the parasites as long as they do not multiply.
bacteria
Bacteria can enter the brain in the case of an ear or sinus infection, for example. Unlike parasites, they are small enough to be eliminated. When microglia perceive typical bacterial components such as lipopeptides, lipopolysaccharides or CpG-DNA with the help of their toll-like receptors (TLRs), they multiply, track down the pathogens and destroy them. Phagocytosis is particularly effective when the bacteria are labeled with complement proteins.
Depending on the local conditions, microglia can protect the surrounding neurons with anti-inflammatory signals or promote inflammation, which can destroy neurons as well as the bacteria. The cytokine Activin A, which is related to TGF-β and is also involved in the remyelination of already damaged neurons, has a neuroprotective effect . On the other hand, by producing nitric oxide and reactive oxygen species, microglia can damage neurons.
Viruses
Viruses are the most common pathogens in the CNS. Because they are hidden inside cells and cannot simply be eliminated by phagocytosis, microglia do not take on the same shape in a viral infection as they do in a sterile injury or bacterial infection. Instead of forming a single thick phagocytic runners, they retain numerous runners, which are shortened and less branched than when they are at rest.
In an acute viral infection, microglia can release numerous pro-inflammatory cytokines and nitric oxide. This inhibits the intracellular replication of the viruses until the more efficient adaptive defense is ready to wipe out the infected cells. To activate antiviral T cells, the microglia increase the expression of the co-stimulators CD40 and CD86 as well as the MHC class I and class II complexes in order to present numerous viral antigens.
Microglia can also be infected by viruses themselves. For example, they are a reservoir for HIV- 1.
Aging
In old mice, the cytoplasm of the microglia is compacted, the cell bodies are larger and the runners are shorter, thicker and less mobile than in young mice. Cell fragments absorbed by phagocytosis accumulate inside them and are no longer broken down properly.
Some of the microglia become senescent, i.e. they can no longer be activated properly and can no longer break down defective neurons and dysfunctional synapses, which contributes to the gradual cognitive decline. Others are overactive: Even without disease, they express more pro-inflammatory cytokines, complement proteins, pattern recognition receptors, reactive oxygen species, etc. than before. At the same time, they produce fewer anti-inflammatory cytokines such as interleukin-10 and TGF-β, fewer activation inhibitors such as CD200 and fewer CX3CL1 receptors. Both favor the development and chronification of inflammations in the CNS.
Neurodegenerative Diseases
Alzheimer's disease , Parkinson's disease , Huntington 's disease , and amyotrophic lateral sclerosis are characterized by abnormal protein aggregates that mainly accumulate in neurons. Due to the phagocytosis of dying neurons, the microglia initially have a neuroprotective effect. Then their ability to break down the misfolded proteins , such as beta-amyloid in Alzheimer's disease, is exhausted .
The accumulation of the aggregates chronically activates microglia; They come under oxidative stress and release substances that promote inflammation, which increase neurodegeneration. In this condition, they no longer respond appropriately to anti-inflammatory cytokines or neural signals.
In mice, such microglia have an electron-dense cytoplasm and nuclear plasma that appear dark under the microscope ; their mitochondria are defective, their endoplasmic reticulum is expanded. Their highly branched, thin runners make contact with the surrounding synapses more often than usual and wrap around presynaptic endings, dendritic thorns or entire synapses.
multiple sclerosis
Microglia are also involved in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis . In the early stages of the disease, an unknown trigger leads to inflammation in the brain. On the one hand, this activates the microglia and causes them to attract monocytes from the blood. On the other hand, the blood-brain barrier becomes permeable, so that autoreactive T-lymphocytes penetrate the brain. Both the macrophages arising from the monocytes and the microglia present them with neuronal autoantigens on their MHC class II complexes , so that the activated T lymphocytes release cytokines that promote inflammation. These cytokines attract other immune cells such as macrophages, dendritic cells, mast cells and B-lymphocytes, which together attack the myelin layer of the neurons. The demyelination eventually causes nerve cells to die.
literature
- Adwitia Dey, Joselyn Allen, Pamela A. Hankey-Giblin: Ontogeny and Polarization of Macrophages in Inflammation: Blood Monocytes Versus Tissue Macrophages . In: Frontiers in Immunology . tape 5 , 2015, ISSN 1664-3224 , doi : 10.3389 / fimmu.2014.00683 .
- Florent Ginhoux, Shawn Lim, Guillaume Hoeffel, Donovan Low, Tara Huber: Origin and differentiation of microglia . In: Frontiers in Cellular Neuroscience . tape 7 , 2013, ISSN 1662-5102 , doi : 10.3389 / fncel.2013.00045 .
- Debasis Nayak, Theodore L. Roth, Dorian B. McGavern: Microglia Development and Function . In: Annual Review of Immunology . tape 32 , no. 1 , March 21, 2014, ISSN 0732-0582 , p. 367-402 , doi : 10.1146 / annurev-immunol-032713-120240 .
- Tuan Leng Tay, Julie C. Savage, Chin Wai Hui, Kanchan Bisht, Marie-Ève Tremblay: Microglia across the lifespan: from origin to function in brain development, plasticity and cognition . In: The Journal of Physiology . tape 595 , no. 6 , March 15, 2017, ISSN 1469-7793 , p. 1929-1945 , doi : 10.1113 / jp272134 .
Individual evidence
- ↑ Ennio Pannese: Neurocytology: Fine Structure of Neurons, Nerve Processes, and Neuroglial Cells . Springer, 2015, ISBN 9783319068565 , p. 225.
- ↑ Travers, Paul, Walport, Mark, Janeway, Charles: Janeway's immunobiology. 7th ed. Garland Science, New York 2008, ISBN 978-0-8153-4123-9 , pp. 624 .