Gliosis
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Gliosis is a nonspecific reactive change of
glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
in response to damage to the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS). In most cases, gliosis involves the proliferation or
hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J ...
of several different types of glial cells, including
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), 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 e ...
s, microglia, and
oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
s. In its most extreme form, the proliferation associated with gliosis leads to the formation of a
glial scar 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 process of gliosis involves a series of cellular and molecular events that occur over several days. Typically, the first response to injury is the migration of
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and local microglia to the injury site. This process, which constitutes a form of gliosis known as microgliosis, begins within hours of the initial CNS injury. Later, after 3–5 days, oligodendrocyte precursor cells are also recruited to the site and may contribute to
remyelination Remyelination is the process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the CNS. This is a process naturally regulated in the body and tends to be very efficient i ...
. The final component of gliosis is
astrogliosis 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, a ...
, the proliferation of surrounding astrocytes, which are the main constituents of the glial scar. Gliosis has historically been given a negative connotation due to its appearance in many CNS diseases and the inhibition of axonal regeneration caused by glial scar formation. However, gliosis has been shown to have both beneficial and detrimental effects, and the balance between these is due to a complex array of factors and molecular signaling mechanisms, which affect the reaction of all glial cell types.


Astrogliosis

Reactive astrogliosis is the most common form of gliosis and involves the proliferation of
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), 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 e ...
s, a type of
glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
responsible for maintaining extracellular ion and
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
concentrations, modulating
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
function, and forming the blood–brain barrier. Like other forms of gliosis, astrogliosis accompanies
traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic b ...
as well as many neuropathologies, ranging from
amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
to
fatal familial insomnia Fatal insomnia is an extremely rare genetic (and even more rarely, sporadic) disorder that results in trouble sleeping as its hallmark symptom. The problems with sleeping typically start out gradually and worsen over time. Eventually, the patien ...
. Although the mechanisms which lead to astrogliosis are not fully understood, neuronal injury is well understood to cause astrocyte proliferation, and astrogliosis has long been used as an index for neuronal damage. Traditionally, astrogliosis has been defined as an increase in intermediate filaments and cellular hypertrophy as well as an increase in the proliferation of astrocytes. Although this
hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J ...
and proliferation in their extreme form are most closely associated with the formation of a
glial scar 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 ...
, astrogliosis is not an all-or-none process in which a glial scar forms. In fact, it is a spectrum of changes that occur based on the type and severity of
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS) injury or disease triggering the event. Changes in astrocyte function or morphology which occur during astrogliosis may range from minor hypertrophy to major hypertrophy, domain overlap, and ultimately, glial scar formation. The severity of astrogliosis is classically determined by the level of expression of glial fibrillary acidic protein (GFAP) and
vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a type III intermediate filament (IF) protein that is expresse ...
, both of which are
upregulated In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...
with the proliferation of active astrocytes.


Modulation of astrogliosis

Changes in astrogliosis are regulated in a context-dependent fashion, and the signaling events which dictate these changes may modify both their nature and severity. It is these changes in astrogliosis which allow the process to be complex and multifaceted, involving both a gain or loss of function as well as both beneficial and detrimental effects. Reactive astrocytes are affected by molecular signals released from a variety of CNS cell types including neurons, microglia, oligodendrocyte precursor cells, leukocytes, endothelia, and even other astrocytes. Some of the many signalling molecules used in these pathways include the
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s interleukin 6 (IL-6), ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF). Although many of these specific modulatory relationships are not yet fully understood, it is known that different specific signaling mechanisms result in different morphological and functional changes of astrocytes, allowing astrogliosis to take on a graduated spectrum of severity.


Effects of astrogliosis

Although astrogliosis has traditionally been viewed as a negative response inhibitory to axonal regeneration, the process is highly conserved, suggesting it has important benefits beyond its detrimental effects. Generally, the effects of astrogliosis vary with the context of the initial CNS insult and also with time after the injury. A few of the most important effects of astrogliosis are listed below.


Beneficial effects

*
Neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
effects – Reactive astrocytes release
neurotrophic factors Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their tro ...
, such as glial cell-derived neurotrophic factor (GDNF), which protects against programmed cell death *Maintenance of the extracellular environment – Astrocytes are responsible for the uptake of
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, which restricts
excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...
to neurons and other cell types, as well as the elimination of
free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spont ...
*Release of
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
molecules *Restoration of blood brain barrier function *Seclusion of the injury site and containment of infection from healthy tissue


Detrimental effects

*Restriction of axon regeneration – In cases of glial scar formation, reactive astrocytes enmesh the
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...
site and deposit an inhibitory
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
consisting of
chondroitin sulfate Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars ( N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have ov ...
proteoglycans. The dense structure of these proteins is a physically and chemically inhibitory barrier to axon regeneration and the reestablishment of axon connections. *Secretion of
neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
substances – These may include
pro-inflammatory Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
and cytotoxic
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s. Examples of these molecules include
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
radicals and
TNF-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
. *Release of excitotoxic glutamate *Hindrance of functional recovery and worsening of clinical signs


Microgliosis

Microglia, another type of glial cell, act as macrophage-like cells in the CNS when activated. Unlike other glial cell types, microglia are extremely sensitive to even small changes in the cellular environment, allowing for a rapid response to inflammatory signals and prompt destruction of infectious agents before sensitive neural tissue can be damaged. Due to their fast response time, microgliosis, or the activation of microglia, is commonly the first observed stage of gliosis. Microgliosis following a CNS insult most commonly involves the development of an altered cellular morphology, specifically the enlargement of cellular processes. The microglial immunological surface receptor CR3 is also upregulated within 24 hours after the initial injury. Within the first week following the injury, microglia begin to proliferate abnormally and while doing so exhibit several immunophenotypic changes, particularly an increased expression of MHC antigens. The population of activated microglia at the site of a CNS injury includes not only endogenous microglia of the CNS but also exogeneous perivascular cells originating in the bone marrow that migrate to the area and transform into microglia to supplement the microgliosis response. While in their activated state, microglia may serve a variety of beneficial functions. For example, active microglia are the primary effectors of
innate immunity The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
and fulfill this role by phagocyting the proteins of dead neurons, presenting
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s at their surface, and producing a variety of pro-inflammatory cytokines and toxic molecules that compromise the survival of surrounding neurons which may be similarly damaged or infected. Active microglia also perform critical
homeostatic In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
activity, including the clearing of cell debris through phagocytosis, a function essential to neuron survival. In addition, active microglia release anti-inflammatory factors and other molecules, such as IL-6 and
TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
, which regulate
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
after injury. However, the over-activation of microglia can also be detrimental by producing several neurotoxic substances including pro-inflammatory factors, such as TNF-α, prostaglandin E2, and
interferon-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
, and
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
factors, including nitric oxide and
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
. Notably, unlike astrogliosis, microgliosis is a temporary and self-limited event, which generally lasts only one month after injury, even in cases of extreme damage.


Neural modulation of microgliosis

Microglial activation has been shown to be a reactive process in which microglia respond to signals given off by injured neurons. Because various characteristics of microgliosis occur in different time frames after the initial triggering insult, microgliosis must depend on mechanisms which fluctuate temporally based on injured neuronal signals. Studies have shown that in cases of reversible neuronal injury, such as axotomy, neuron signals cause microglia to produce trophic factors, which promote neuron survival. In cases of irreversible injury, however, microglia are induced to release neurotoxic factors that promote increased degeneration of the neuron and more rapid phagocytosis by the microglia. Such specificity of the process of microgliosis indicates that it primarily serves a beneficial purpose, selectively conserving some neural tissue while eliminating others, based on the specific initial CNS insult.


Microglial regulation of astrogliosis

Although the molecular triggers of gliosis, including both astrogliosis and microgliosis, are not fully understood, in vitro studies have indicated that activated microglia have an important role in initiating and modulating astrogliosis. One critical piece of evidence supporting this relationship is the widely documented temporal correlation between the onsets of the two processes. Unlike the microglial response, which occurs rapidly, the start of astrogliosis is often delayed. A likely cause of this relationship is the pro-inflammatory cytokines and chemokines released at elevated levels by microglia upon activation. These include macrophage inflammatory protein-1 (MIP), macrophage colony stimulating factor (M-CSF), the interleukins IL-1, IL-6, and IL-8, and TNF-α. Receptors for these molecules have been identified on astrocytes, and the molecules, when exogenously introduced, have been shown to induce, enhance, or accompany astrogliosis. Astrocytes themselves also produce cytokines, which may be used for self-regulation or for the regulation of microglia, which contain similar cytokine receptors. This phenomenon creates a
feedback loop Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause-and-effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handled c ...
, allowing both microglia and astrocytes to regulate one another. In addition, evidence suggests microglial regulation of astrogliosis may also include inhibitory effects. Reduced levels of microgliosis have been associated with reduced astrocyte numbers, which also suggests that microglia are important regulators of the degree of astrocyte activation.


Response of oligodendrocytes

Oligodendrocytes Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
are another type of glial cell which generate and maintain the formation of
myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
around the
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
s of large neurons in the CNS, allowing for rapid transmission of neural signals. Unlike astrocytes and microglia, oligodendrocytes undergo a much more limited reaction to injury. Rather, in cases of CNS trauma, they are more similar to neurons in their susceptibility to sustaining damage. The degeneration of axons as a result of trauma or pathology invariably results in the degeneration of the myelin sheath. Depending on the mechanism of insult, several different patterns of oligodendrocyte injury and reaction may be observed. In all cases, however, some oligodendrocytes are lost, through
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
or
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, while others survive and may form part of the glial scar along with myelin debris. Oligodendrocyte precursor cells are also affected by CNS insult and are recruited to demyelinated areas within a week following traumatic injury. Some of these cells may produce new myelin when exposed to signals from activated microglia and astrocytes.


Triggers of gliosis

In general after any CNS insult, gliosis begins after the blood brain barrier is disrupted, allowing non-CNS molecules, such as blood and serum components, to enter the brain. These components, along with activated
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
they carry, are known to have a role in beginning the formation of the glial scar by inducing the disconnection of axons, also called secondary axotomy, and the upregulation of fibrous extracellular matrix components which eventually form the scar tissue. The specific molecular triggers responsible for this action, however, remain unknown. One potential trigger is transforming growth factor β (TGF-β). TGF-β2, whose expression is gradually increased as gliosis occurs, has been shown to increase astrocyte production of scar-forming proteoglycans. Experimental reduction of both TGF-β2 and TGF-β1, which is expressed immediately after injury, has resulted in reduced glial scarring. The interleukins are another potential molecular trigger of gliosis. These molecules, notably IL-1, initiate an inflammatory response in various cells including astrocytes that contributes to the gliosis reaction. Finally, interactions between the inflammatory cytokines interferon-γ (IFN-γ) and fibroblast growth factor 2 (FGF2) may also be responsible for the induction of gliosis. In culture, both molecules act as
mitogen A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
s, prompting the proliferation of astrocytes. Moreover, addition of IFN-γ to brain lesion sites has resulted in an increase in glial scarring.


In CNS injury and disease

Gliosis is the universal response of the CNS to tissue injury and occurs as a result of many acute conditions such as trauma,
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
, and
stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
. Additionally, gliosis is present in a wide variety of CNS pathologies, including
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, Korsakoff's syndrome, multiple system atrophy,
prion disease Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It i ...
,
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
,
AIDS dementia complex HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during ...
,
vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused ...
,
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
,
amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
, and
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
. In every case, gliosis involves some degree of hypertrophy or proliferation of glial cells, but the extent and nature of the gliosis response vary widely based on the triggering insult. Gliosis in any form entails an alteration in cellular activity that has the potential to create widespread effects on neurons as well as other non-neural cells, causing either a loss of normal functions or a gain of detrimental ones. In this light, gliosis may be seen not only as a characteristic of many neuropathologies but as a potential contributor to, or even cause of, many CNS disease mechanisms. A select group of CNS conditions associated with gliosis are described below.


CNS trauma

Acute trauma to the
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
or
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
results in gliosis, most often in its severe form with the development of a glial scar. Different locations around the lesion site may exhibit different severities of gliosis; for example, a glial scar at the location of damaged tissue may be surrounded by areas with less severe astrocyte proliferation or hypertrophy. Diffuse traumatic injury can result in diffuse or more moderate gliosis without scar formation. In such cases, gliosis may also be reversible. In all instances of gliosis resulting from CNS trauma, the long-term clinical outcome is highly dependent on the degree of astrogliosis and scar formation.


Multiple sclerosis and autoimmune inflammatory disorders

Gliosis is a prominent feature of many
autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
inflammatory disorders, notably
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, in which demyelinated plaques are surrounded by reactive astrocytes. These astrocytes often exhibit extreme hypertrophy and multiple distinct nuclei, and their production of pro-inflammatory molecules has been implicated in several inflammatory disorders. Cytokines produced by both active astrocytes and microglia in inflammatory conditions may contribute to myelin damage and may alter blood-brain barrier permeability, allowing the migration of
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s into the CNS and heightening the autoimmune attack.


Retinal gliosis

In vertebrates, the retina contains Müller cells, a type of glia not found elsewhere in the CNS. Upon retinal injury, gliosis of these cells occurs, functioning to repair damage, but often having harmful consequences in the process, worsening some of the diseases or problems that initially trigger it. Reactive gliosis in the retina can have detrimental effects on vision; in particular, the production of proteases by astrocytes causes widespread death of retinal ganglion cells. A 2011 study compared the effects of two glial toxins, AAA and Neurostatin, on retinal gliosis in mice. AAA did not inhibit the production of protease by astrocytes, and so did not prevent ganglion cell apoptosis. However, Neurostatin successfully inhibited activation of astrocytes, in turn decreasing retinal ganglion cell death significantly. Neurostatin is also effective in the inhibition of other glial cells, and may be an area of interest in the treatment of degenerative diseases such as glaucoma. Massive retinal gliosis (MRG) is a phenomenon in which the retina is completely replaced by proliferation of glial cells, causing deterioration of vision and even blindness in some cases. Sometimes mistaken for an intraocular tumor, MRG can arise from a neurodegenerative disease, congenital defect, or from trauma to the eyeball, sometimes appearing years after such an incident.


Alzheimer's disease

Gliosis has long been known as a characteristic of Alzheimer's Disease (AD), although its exact role in the disease remains unknown. Gliosis and glial scarring occur in areas surrounding the amyloid plaques which are hallmarks of the disease, and postmortem tissues have indicated a correlation between the degree of astrogliosis and cognitive decline. Exposure of reactive astrocytes to β-amyloid (Αβ) peptide, the main component of amyloid plaques, may also induce astroglial dysfunction and neurotoxicity. In addition, the ability of reactive astrocytes to degrade extracellular Αβ deposits may suggest that astrogliosis may affect the progression or severity of AD.


Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a debilitating disease involving the degeneration of
motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...
s in the CNS. Reactive astrocytes have been implicated in this condition through either a loss of their neuroprotective ability or through the gain of neurotoxic effects. Late stages of ALS are also characterized by significant astrogliosis and astrocyte proliferation around areas of degeneration.


Potential therapeutic targets in gliosis

The implications of gliosis in various neuropathologies and injury conditions has led to the investigation of various therapeutic routes which would regulate specific aspects of gliosis in order to improve clinical outcomes for both CNS trauma and a wide range of neurological disorders. Because gliosis is a dynamic process which involves a spectrum of changes depending on the type and severity of the initial insult, to date, no single molecular target has been identified which could improve healing in all injury contexts. Rather, therapeutic strategies for minimizing the contribution of astrogliosis to CNS pathologies must be designed to target specific molecular pathways and responses. One promising therapeutic mechanism is the use of
β-lactam antibiotics β-lactam antibiotics (beta-lactam antibiotics) are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and ...
to enhance the glutamate uptake of astrocytes in order to reduce excitotoxicity and provide neuroprotection in models of stroke and ALS. Other proposed targets related to astrogliosis include manipulating AQP4 channels, diminishing the action of NF-kB, or regulating the
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...
pathway in order to reduce the inflammatory effects of reactive astrocytes. Astrogliosis may also be attenuated by inhibiting the microgliosis response. One notable microglial activation inhibitor is
minocycline Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as pneumonia. It is generally less preferred than the tetracycline doxycycline. It is also ...
, which is a known suppressor of astrogliosis. The cell cycle inhibitor olomoucine also has been shown to suppress both microglial and astroglial proliferation as well as glial scar formation. Future directions for identifying novel therapeutic strategies must carefully account for the complex array of factors and signaling mechanisms driving the gliosis response, particularly in different stages after damage and in different lesion conditions.


See also

* Bergmann gliosis


References


External links

{{Medical resources , ICD10 = {{ICD10, G93.8, {{ICD10, G95.8 Brain disorders Glial cells Medical terminology