Astrogliosis

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Astrogliosis
Reactive astrocytes - lfb - high mag.jpg
Formation of reactive astrocytes after central nervous system (CNS) injury
Anatomical terminology

Astrogliosis (also known as astrocytosis or referred to as reactive astrogliosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. [1] [2] Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration. [3] [4]

Contents

Causes

Reactive astrogliosis is a spectrum of changes in astrocytes that occur in response to all forms of CNS injury and disease. Changes due to reactive astrogliosis vary with the severity of the CNS insult along a graduated continuum of progressive alterations in molecular expression, progressive cellular hypertrophy, proliferation and scar formation. [3]

Insults to neurons in the central nervous system caused by infection, trauma, ischemia, stroke, recurring seizures, autoimmune responses, or other neurodegenerative diseases may cause reactive astrocytes. [2]

When the astrogliosis is pathological itself, instead of a normal response to a pathological problem, it is referred to as astrocytopathy. [5]

Functions and effects

Reactive astrocytes may benefit or harm surrounding neural and non-neural cells. They undergo a series of changes that may alter astrocyte activities through gain or loss of functions lending to neural protection and repair, glial scarring, and regulation of CNS inflammation. [3]

Neural protection and repair

Proliferating reactive astrocytes are critical to scar formation and function to reduce the spread and persistence of inflammatory cells, to maintain the repair of the blood–brain barrier (BBB), to decrease tissue damage and lesion size, and to decrease neuronal loss and demyelination. [6] [7]

Reactive astrocytes defend against oxidative stress through glutathione production and have the responsibility of protecting CNS cells from NH4+ toxicity. [3] They protect CNS cells and tissue through various methods, [3] [8] [9] such as uptake of potentially excitotoxic glutamate, adenosine release, and degradation of amyloid β peptides. [3] The repair of a disruption in the blood brain barrier is also facilitated by reactive astrocytes by their direct endfeet (characteristic structure of astrocytes) interaction with blood vessel walls that induce blood brain barrier properties. [8]

They have also been shown to reduce vasogenic edema after trauma, stroke, or obstructive hydrocephalus. [3]

Scar formation

Proliferating reactive scar-forming astrocytes are consistently found along borders between healthy tissues and pockets of damaged tissue and inflammatory cells. This is usually found after a rapid, locally triggered inflammatory response to acute traumatic injury in the spinal cord and brain. In its extreme form, reactive astrogliosis can lead to the appearance of newly proliferated astrocytes and scar formation in response to severe tissue damage or inflammation.

Molecular triggers that lead to this scar formation include epidermal growth factor (EGF), fibroblast growth factor (FGF), endothelin 1 and adenosine triphosphate (ATP). Mature astrocytes can re-enter the cell cycle and proliferate during scar formation. Some proliferating reactive astrocytes can derive from NG2 progenitor cells in the local parenchyma from ependymal cell progenitors after injury or stroke. There are also multipotent progenitors in subependymal tissue that express glial fibrillary acidic protein (GFAP) and generate progeny cells that migrate towards sites of injury after trauma or stroke. [10]

Regulation of inflammation

Reactive astrocytes are related to the normal function of astrocytes. Astrocytes are involved in the complex regulation of CNS inflammation that is likely to be context-dependent and regulated by multimodal extra- and intracellular signaling events. They have the capacity to make different types of molecules with either pro- or anti-inflammatory potential in response to different types of stimulation. Astrocytes interact extensively with microglia and play a key role in CNS inflammation. Reactive astrocytes can then lead to abnormal function of astrocytes and affect their regulation and response to inflammation. [10] [11]

Pertaining to anti-inflammatory effects, reactive scar-forming astrocytes help reduce the spread of inflammatory cells during locally initiated inflammatory responses to traumatic injury or during peripherally-initiated adaptive immune responses. [3] [8] In regard to pro-inflammatory potential, certain molecules in astrocytes are associated with an increase in inflammation after traumatic injury. [3]

At early stages after insults, astrocytes not only activate inflammation, but also form potent cell migration barriers over time. These barriers mark areas where intense inflammation is needed and restrict the spread of inflammatory cells and infectious agents to nearby healthy tissue. [3] [7] [8] CNS injury responses have favored mechanisms that keep small injuries uninfected. Inhibition of the migration of inflammatory cells and infectious agents have led to the accidental byproduct of axon regeneration inhibition, owing to the redundancy between migration cues across cell types. [3] [7]

Biological mechanisms

Changes resulting from astrogliosis are regulated in a context-specific manner by specific signaling events that have the potential to modify both the nature and degree of these changes. Under different conditions of stimulation, astrocytes can produce intercellular effector molecules that alter the expression of molecules in cellular activities of cell structure, energy metabolism, intracellular signaling, and membrane transporters and pumps. [10] [12] Reactive astrocytes respond according to different signals and impact neuronal function. Molecular mediators are released by neurons, microglia, oligodendrocyte lineage cells, endothelia, leukocytes, and other astrocytes in the CNS tissue in response to insults ranging from subtle cellular perturbations to intense tissue injury. [3] The resulting effects can range from blood flow regulation to provision of energy to synaptic function and neural plasticity.

Reactive astrocytes in a rat brain stained against GFAP. 2010-3-15 rGFAP 1-4000 1-200 Hip 20x(4).tif
Reactive astrocytes in a rat brain stained against GFAP.

Signaling molecules

Few of the known signaling molecules and their effects are understood in the context of reactive astrocytes responding to different degrees of insult.

Upregulation of GFAP, which is induced by FGF, TGFB, and ciliary neurotrophic factor (CNTF), is a classic marker for reactive gliosis. [2] [13] Axon regeneration does not occur in areas with an increase in GFAP and vimentin. Paradoxically, an increase in GFAP production is also specific to the minimization of the lesion size and reduction in the risk for autoimmune encephalomyelitis and stroke. [13]

Transporters and channels

The presence of astrocyte glutamate transporters is associated with a reduced number of seizures and diminished neurodegeneration whereas the astrocyte gap junction protein Cx43 contributes to the neuroprotective effect of preconditioning to hypoxia. In addition, AQP4, an astrocyte water channel, plays a crucial role in cytotoxic edema and aggravate outcome after stroke. [3]

Neurological pathologies

Loss or disturbance of functions normally performed by astrocytes or reactive astrocytes during the process of reactive astrogliosis has the potential to underlie neural dysfunction and pathology in various conditions including trauma, stroke, multiple sclerosis, and others. Some of the examples are as follows: [3]

Reactive astrocytes may also be stimulated by specific signaling cascades to gain detrimental effects such as the following: [3] [14]

Reactive astrocytes have the potential to promote neural toxicity via the generation cytotoxic molecules such as nitric oxide radicals and other reactive oxygen species, [7] which may damage nearby neurons. Reactive astrocytes may also promote secondary degeneration after CNS injury. [7]

Novel therapeutic techniques

Due to the destructive effects of astrogliosis, which include altered molecular expression, release of inflammatory factors, astrocyte proliferation and neuronal dysfunction, researchers are currently searching for new ways to treat astrogliosis and neurodegenerative diseases. Various studies have shown the role of astrocytes in diseases such as Alzheimer's, amyotrophic lateral sclerosis (ALS), Parkinson's, and Huntington's. [15] The inflammation caused by reactive astrogliosis augments many of these neurological diseases. [16] Current studies are researching the possible benefits of inhibiting the inflammation caused by reactive gliosis in order to reduce its neurotoxic effects.

Neurotrophins are currently being researched as possible drugs for neuronal protection, as they have been shown to restore neuronal function. For example, a few studies have used nerve growth factors to regain some cholinergic function in patients with Alzheimer's. [15]

Anti-gliosis function of BB14

One specific drug candidate is BB14, which is a nerve growth factor-like peptide that acts as a TrkA agonist. [15] BB14 was shown to reduce reactive astrogliosis following peripheral nerve injuries in rats by acting on DRG and PC12 cell differentiation. [15] Although further research is needed, BB14 has the potential to treat a variety neurological diseases. Further research of neurotrophins could potentially lead to the development of a highly selective, potent, and small neurotrophin that targets reactive gliosis to alleviate some neurodegenerative diseases.

Regulatory function of TGFB

TGFB is a regulatory molecule involved in proteoglycan production. This production is increased in the presence of bFGF or Interleukin 1. An anti-TGFβ antibody may potentially reduce GFAP upregulation after CNS injuries, promoting axonal regeneration. [2]

Ethidium bromide treatment

Injection of ethidium bromide kills all CNS glia (oligodendrocytes and astrocytes), but leaves axons, blood vessels, and macrophages unaffected. [2] [4] This provides an environment conducive to axonal regeneration for about four days. After four days, CNS glia reinvade the area of injection and axonal regeneration is consequently inhibited. [2] This method has been shown to reduce glial scarring following CNS trauma. [4]

Metalloprotinease activity

Oligodendrocyte precursor cells and C6 glioma cells produce metalloproteinase, which is shown to inactivate a type of inhibitory proteoglycan secreted by Schwann cells. Consequently, increased metalloproteinase in the environment around axons may facilitate axonal regeneration via degradation of inhibitory molecules due to increased proteolytic activity. [2]

Related Research Articles

<span class="mw-page-title-main">Nervous tissue</span> Main component of the nervous system

Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain and spinal cord, and the peripheral nervous system (PNS) comprising the branching peripheral nerves. It is composed of neurons, also known as nerve cells, which receive and transmit impulses, and neuroglia, also known as glial cells or glia, which assist the propagation of the nerve impulse as well as provide nutrients to the neurons.

<span class="mw-page-title-main">Glia</span> Support cells in the nervous system

Glia, also called glial cells(gliocytes) or neuroglia, are non-neuronal cells in the central nervous system and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells, and microglia, and in the peripheral nervous system they include Schwann cells and satellite cells.

<span class="mw-page-title-main">Astrocyte</span> Type of brain cell

Astrocytes, also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, regulation of cerebral blood flow, and a role in the repair and scarring process of the brain and spinal cord following infection and traumatic injuries. The proportion of astrocytes in the brain is not well defined; depending on the counting technique used, studies have found that the astrocyte proportion varies by region and ranges from 20% to 40% of all glia. Another study reports that astrocytes are the most numerous cell type in the brain. Astrocytes are the major source of cholesterol in the central nervous system. Apolipoprotein E transports cholesterol from astrocytes to neurons and other glial cells, regulating cell signaling in the brain. Astrocytes in humans are more than twenty times larger than in rodent brains, and make contact with more than ten times the number of synapses.

<span class="mw-page-title-main">Glial fibrillary acidic protein</span> Type III intermediate filament protein

Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the GFAP gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astrocytes and ependymal cells during development. GFAP has also been found to be expressed in glomeruli and peritubular fibroblasts taken from rat kidneys, Leydig cells of the testis in both hamsters and humans, human keratinocytes, human osteocytes and chondrocytes and stellate cells of the pancreas and liver in rats.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 7% 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 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.

<span class="mw-page-title-main">Rostral migratory stream</span> One path neural stem cells take to reach the olfactory bulb


The rostral migratory stream (RMS) is a specialized migratory route found in the brain of some animals along which neuronal precursors that originated in the subventricular zone (SVZ) of the brain migrate to reach the main olfactory bulb (OB). The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain as compared to the human brain, as our olfactory sense is not as developed. This pathway has been studied in the rodent, rabbit, and both the squirrel monkey and rhesus monkey. When the neurons reach the OB they differentiate into GABAergic interneurons as they are integrated into either the granule cell layer or periglomerular layer.

<span class="mw-page-title-main">Neuroimmune system</span>

The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.

Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.

<span class="mw-page-title-main">Radial glial cell</span> Bipolar-shaped progenitor cells of all neurons in the cerebral cortex and some glia

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.

<span class="mw-page-title-main">Glia limitans</span> Thin astrocyte membrane surrounding the brain and spinal cord

The glia limitans, or the glial limiting membrane, is a thin barrier of astrocyte foot processes associated with the parenchymal basal lamina surrounding the brain and spinal cord. It is the outermost layer of neural tissue, and among its responsibilities is the prevention of the over-migration of neurons and neuroglia, the supporting cells of the nervous system, into the meninges. The glia limitans also plays an important role in regulating the movement of small molecules and cells into the brain tissue by working in concert with other components of the central nervous system (CNS) such as the blood–brain barrier (BBB).

<span class="mw-page-title-main">Satellite glial cell</span>

Satellite glial cells, formerly called amphicytes, are glial cells that cover the surface of neuron cell bodies in ganglia of the peripheral nervous system. Thus, they are found in sensory, sympathetic, and parasympathetic ganglia. Both satellite glial cells (SGCs) and Schwann cells are derived from the neural crest of the embryo during development. SGCs have been found to play a variety of roles, including control over the microenvironment of sympathetic ganglia. They are thought to have a similar role to astrocytes in the central nervous system (CNS). They supply nutrients to the surrounding neurons and also have some structural function. Satellite cells also act as protective, cushioning cells. Additionally, they express a variety of receptors that allow for a range of interactions with neuroactive chemicals. Many of these receptors and other ion channels have recently been implicated in health issues including chronic pain and herpes simplex. There is much more to be learned about these cells, and research surrounding additional properties and roles of the SGCs is ongoing.

<span class="mw-page-title-main">Gemistocyte</span> Swollen and reactive astrocyte

A gemistocyte is a swollen, reactive astrocyte.

Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

<span class="mw-page-title-main">Subgranular zone</span>

The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

<span class="mw-page-title-main">Glial scar</span> Mass formed in response to injury to the nervous system

Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system.

Endogenous regeneration in the brain is the ability of cells to engage in the repair and regeneration process. While the brain has a limited capacity for regeneration, endogenous neural stem cells, as well as numerous pro-regenerative molecules, can participate in replacing and repairing damaged or diseased neurons and glial cells. Another benefit that can be achieved by using endogenous regeneration could be avoiding an immune response from the host.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier.

<span class="mw-page-title-main">Neuronal lineage marker</span> Endogenous tag expressed in different cells along neurogenesis and differentiated cells

A neuronal lineage marker is an endogenous tag that is expressed in different cells along neurogenesis and differentiated cells such as neurons. It allows detection and identification of cells by using different techniques. A neuronal lineage marker can be either DNA, mRNA or RNA expressed in a cell of interest. It can also be a protein tag, as a partial protein, a protein or an epitope that discriminates between different cell types or different states of a common cell. An ideal marker is specific to a given cell type in normal conditions and/or during injury. Cell markers are very valuable tools for examining the function of cells in normal conditions as well as during disease. The discovery of various proteins specific to certain cells led to the production of cell-type-specific antibodies that have been used to identify cells.

References

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