Gliosis

Reactive astrogliosis is the most common form of gliosis and involves the proliferation of astrocytes, a type of glial cell responsible for maintaining extracellular ion and neurotransmitter concentrations, modulating synapse function, and forming the blood–brain barrier. Like other forms of gliosis, astrogliosis accompanies traumatic brain injury as well as many neuropathologies, ranging from amyotrophic lateral sclerosis to fatal familial insomnia. 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 and proliferation in their extreme form are most closely associated with the formation of a glial scar, 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 (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. 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. • Release of anti-inflammatory 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 site and deposit an inhibitory extracellular matrix consisting of chondroitin sulfate 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 substances – These may include pro-inflammatory and cytotoxic cytokines. Examples of these molecules include nitric oxide radicals and TNF-α. • 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. While in their activated state, microglia may serve a variety of beneficial functions. For example, active microglia are the primary effectors of innate immunity and fulfill this role by phagocyting the proteins of dead neurons, presenting antigens 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. 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, 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 are another type of glial cell which generate and maintain the formation of myelin around the axons 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. ==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. 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, and stroke. Additionally, gliosis is present in a wide variety of CNS pathologies, including Alzheimer's disease, Korsakoff's syndrome, multiple system atrophy, prion disease, multiple sclerosis, AIDS dementia complex, vasculitis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. 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. 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 neurons 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 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 pathway in order to reduce the inflammatory effects of reactive astrocytes. ==See also==