Astrocytes are activated by various insults to the brain, such as trauma, ischemia and neurodegenerative disease, and respond via the process of astrogliosis. In the damaged brain, reactive astrocytes show different morphological features and expression of genes compared with normal astrocytes in order to protect and repair the injured brain (Eddleston and Mucke, 1993;Eng and Ghirnikar, 1994;Hernandez, et al., 2002;Pekny and Nilsson, 2005).
1. Reactive astrocytes: intermediate filaments (IFs) and morphological features
In the injured brain, astrocytes show high expression of intermediate filaments (IFs) such as glial fibrillary acidic protein (GFAP), nestin and vimentin. In particular, GFAP is the primary intermediate filament of astrocytes and has been used as a hallmark of reactive astrocytes in the injured brain (Correa-Cerro and Mandell, 2007;Eddleston and Mucke, 1993;Eng, et al., 2000). GFAP and the other IFs of reactive astrocytes are seen in a wide range of brain insults such as trauma, ischemic or hemorrhagic damage, epilepsy,
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Alzheimer's disease, PD and multiple sclerosis (Burda and Sofroniew, 2014). Interestingly, a lack of GFAP and other IFs leads to the induction of neuronal damage by traumatic cerebrospinal injury, cerebral ischemia and traumatic or kainate excitotoxicity (Li, et al., 2008;Nawashiro, et al., 2000;Nawashiro, et al., 1998;Otani, et al., 2006).
Upregulated IFs cause morphological changes in reactive astrocytes such as hypertrophy of the cell body, and thickening and extension of the cellular processes (Wilhelmsson, et al., 2004). In a GFAP and vimentin dual KO mouse model, reactive astrocytes demonstrated less hypertrophy, process shortening and a reduction of glial scar formation when compared with WT.
2. Reactive astrocytes: function of astrogliosis in neural protection
Reactive astrocytes construct a physical barrier around damaged core regions with microglia/macrophages, extracellular matrix molecules, perivascular fibroblasts and pericytes, to isolate the site of injury (Burda and Sofroniew, 2014;Cregg, et al., 2014;Rolls, et al., 2009). After injury, the number of reactive astrocytes increases and surrounds the damaged core region (Fitch and Silver, 1997;Reier and Houle, 1988). Moreover, reactive astrocytes eliminate increased extracellular glutamate after injury (Rothstein, et al., 1996;Swanson, et al., 2004). Ablation of reactive astrocytes leads to a reduction in glutamate transporter expression and an induction of neuronal degeneration due to the excitotoxic effects of accumulating glutamate (Cui, et al., 2001). In addition, reactive astrocytes regulate oxidative stress after injury (Desagher, et al., 1996). For example, neuronal death due to nitric oxide (NO) or oxidative glutamate toxeicity was increased in a co-culture system with
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glutathione deficient astrocytes (Chen, et al., 2001;Shih, et al., 2003). Reactive astrocytes also provide neuronal protection against ammonia toxicity. Ammonia, CNS dysfunction associated neurotoxin with hepatic encephalopathy, induced extensive degeneration in pure neuron culture. However, extensive degeneration was decreased in co-culture system with astrocytes (Rao, et al., 2005).
3. Reactive astrocytes: function of astrogliosis for regeneration and repair
In the past, various studies have suggested the potential negative effects of astrogliosis scar formation such as the elimination of neural regeneration. Numerous therapeutic studies have reported that the degradation of scar formation through techniques such as enzymes to eliminate scar formation (Moon, et al., 2001;Tester and Howland, 2008), and inhibition of astrocyte proliferation (Tian, et al., 2007), led to beneficial effects for regeneration. However, growing evidence has demonstrated that astrogliosis has important roles in regeneration and repair by regulating the supply of nutrients, angiogenesis, remyelination, neurotrophic factor s and neurogenesis (do Carmo Cunha, et al., 2007;Liberto, et al., 2004;Triolo, et al., 2006;White, et al., 2008). Reactive astrocytes showed increased glucose uptake and lactate release in hypoxic conditions (Marrif and Juurlink, 1999) and stored glycogen following stimulation by insulin-like growth factor-1 (IGF-1) (Dringen and Hamprecht, 1992) to provide energy support for neighboring neurons. In addition, astrocytes are associated with fibronectin, which outgrowth of dorsal root ganglion (DRG) neurites and axon regeneration in mature white matter (Tom, et al., 2004). Reactive astrocytes also correlated with neovascularization and angiogenesis, which provide oxygen and nutrients to
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the injured brain area. Vascular endothelial growth factor (VEGF) is a key molecule in angiogenesis and is induced by platelet-activating factor (PAF) from reactive astrocytes after stab wounds, neural grafting and hypoxia (Krum and Rosenstein, 1998;Yoshida, et al., 2002).
Reactive astrocytes also correlates with remyelination. Ciliary neurotrophic factor (CNTF) has been shown to regulate the induction of oligodendrocyte precursor proliferation through fibroblast growth factor-2 (FGF-2) for remyelination (Albrecht, et al., 2003). Interestingly, the levels of CNTF, which is present in normal astrocytes, were highly increased in reactive astrocytes after brain injury (Dallner, et al., 2002). In addition, CNTF induced FGF-2 expression in reactive astrocytes during remyelination in the spinal cord (Albrecht, et al., 2003). Moreover, it has been reported that reactive astrocytes express neurotrophic factor.
For example, glial cell line-derived neurotrophic factor (GDNF) and its receptors are expressed during development and in the adult brain (Arenas, et al., 1995;Buj-Bello, et al., 1995;Oppenheim, et al., 1995). GDNF reported to effect neuronal survival (Kordower, et al., 2000;Perrelet, et al., 2002) and axonal regeneration (Bjorklund, et al., 1997;Iannotti, et al., 2003;Mills, et al., 2007). It has been reported that reactive astrocytes also express GDNF (Moretto, et al., 1996;Nakagawa and Schwartz, 2004). Recently, detection of reactive astrocyte derived neural stem and progenitor cells suggest that reactive astrocytes have stem cell-like properties after brain injury (Gotz, et al., 2015;Shimada, et al., 2012), since neural stem cell-like cells have been found in cortical tissues after various injuries such as stabbing injuries and stroke (Buffo, et al., 2008;Nakagomi, et al., 2009;Shimada, et al., 2010).
Reactive astrocytes also express several stem cell associated protein such as GFAP, Nestin, RC2 and Sox2 (Buffo, et al., 2008;Pekny and Pekna, 2004;Shimada, et al., 2010).
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Furthermore, glutamate aspartate transporter (GLAST)-positive reactive astrocytes showed de-differentiation and multipotent spheres formation potential (Buffo, et al., 2008).
4. Reactive astrocytes: function of astrogliosis for regulation of inflammation
Brain inflammation is a critical defense mechanism and process to regenerate the microenvironment after brain injury through the action of microglia and infiltrating marcrophages. Microglia and macrophages produce neurotrophic factors, such as transforming growth factor (TGF)-b1, neurotrophin (NT)-3 and brain-derived neurotrophic factor (BDNF). (Batchelor, et al., 1999;Elkabes, et al., 1996;Garg, et al., 2008;Glezer, et al., 2007;Jeong, et al., 2013a;Jeong, et al., 2013b;Lehrmann, et al., 1998;Schwartz, et al., 2006;Streit, 2005;Streit, 2002). However, uncontrolled brain inflammation could accelerate the progression of injury (Chao, et al., 1992;Choi, et al., 2003;Kitamura, et al., 1996). Many studies suggest that brain inflammation is a risk factor for neurodegenerative diseases such as Alzheimer's disease (AD), PD, and multiple sclerosis (MS) (Breitner, 1996;Chen, et al., 2003;Klegeris and McGeer, 2005;Raivich and Banati, 2004;Sheng, et al., 1998). Therefore, brain inflammation is tightly regulated to maintain its beneficial effects.
Following numerous studies, it has been demonstrated that astrocytes or reactive astrocyte have essential anti-inflammatory roles (Sofroniew, 2015). For example, astrocytes release various cytokines such as TGF-b, IL-6, IL-10, IL-11 IL-19, and IL-27 which activate anti-inflammatory signaling and immunosuppressive effects (Jensen, et al., 2013;John, et al., 2005;Meeuwsen, et al., 2003;Zamanian, et al., 2012). Furthermore astrocytes also produce prostaglandins E2 (PGE2) as an anti-inflammatory factor (Molina-Holgado, et al., 2000) and
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astrocyte-conditioned media (ACM) suppresses nitrite, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-a expression in IFN-g treated BV2, primary microglia.
ACM also induced endogenous NRF2 translocation and HO-1 expression. (Min KJ et al., 2006). In addition, several studies have suggested that the inflammatory response is increased in astrogliosis ablated transgenic mice after stroke (Li, et al., 2008;Liu, et al., 2014) and spinal cord injury (Herrmann, et al., 2008;Okada, et al., 2006).