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Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system
Life Sciences 89 (2011) 141–146
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Life Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / l i f e s c i e
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Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system W. Liu a,⁎, Y. Tang b,⁎, J. Feng c a b c
Department of Physiology, College of fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China Department of Neurology, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China Department of Physiology, Zhongshan Medical College, Sun Yat-sen University, Guangzhou, 510080, PR China
a r t i c l e
i n f o
Article history: Received 1 January 2011 Accepted 26 May 2011 Keywords: Astrocyte Microglia Activation Cross talk ATP IL-1 TGF-β
a b s t r a c t Microglia and astrocytes in the central nervous system are now recognized as active participants in various pathological conditions such as trauma, stroke, or chronic neurodegenerative disorders. Their activation is closely related with the development and severity of diseases. Interestingly, activation of microglia and astrocytes occurs with a spatially and temporarily distinct pattern. The present review explores the cross talk in the process of their activation. Microglia, activated earlier than astrocytes, promote astrocytic activation. On the other hand, activated astrocytes not only facilitate activation of distant microglia, but also inhibit microglial activities. Molecules contributing to their intercommunication include interleukin-1 (IL-1), adenosine triphosphate (ATP), and transforming growth factor beta (TGF-β). A better understanding about the cross talk between activation of microglia and astrocytes would be helpful to elucidate the role of glial cells in pathological conditions, which could accelerate the development of treatment for various diseases. © 2011 Elsevier Inc. All rights reserved.
Contents Microglia and astrocytes . . . . . . . . . . . . . . . . . . . . . . . . Microglia are activated earlier than astrocytes . . . . . . . . . . . . . . Activated microglia promote astrocytic activation. . . . . . . . . . . . . Activated astrocytes facilitate distant microglial activation via calcium wave Activated astrocytes can also inhibit microglial activities . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Microglia and astrocytes Glia in the central nervous system (CNS) mainly include microglia, astrocytes and oligodendrocytes. Here we mainly talk about microglia and astrocytes, both of which are activated in pathological conditions. Originally they were merely regarded as structural support for neurons. However, more and more evidence indicates that glial cells
⁎ Corresponding authors at: Department of Physiology, College of fundamental Medical Science, Guangzhou University of Chinese Medicine, University Town of Guangzhou, Panyu District, Guangzhou, 510006, PR China. Tel.: + 86 20 39358028. E-mail address: [email protected] (W. Liu). 0024-3205/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2011.05.011
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are active and responsive to environmental changes (being activated). Generally, activation refers to an enhanced ability of a cell to perform a function beyond that present in basal state. For microglia and astrocytes, their activation is multi-dimensional, that is, they proliferate, phagocytose, and release proinflammatory cytokines or growth factors (Kettenmann and Verkhratsky, 2008). Meantime, the cross talk between activated glial cells and neurons has been becoming the focus for these two decades. Neuron can activate glia via various neurotransmitters or modulators, such as glutamate, fractalkine, nitric oxide (NO) and others (Liu et al., 2006; Verge et al., 2004). Conversely, the activated glial cells affect neuronal function and contribute to the development of various diseases such as neurodegenerative diseases, ischemia, and injury. This happens in the process of clearing bacteria or virus, releasing proinflammatory cytokines and neurotrophic factors,
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and forming glial scars. However, whether there are intercommunications between microglia and astrocytes remain to be elucidated. Microglia, constituting around 10–20% of all glial cells, they are derived from bone marrow precursors and represent the brain's internal immune system, thus being considered as the first line of defense. In physiological condition, microglia are ramified and have highly motile processes, surveiling the microenvironment in CNS (Nimmerjahn et al., 2005). Once there are abnormal substances, such as cell necrosis factors, lipopolysaccharide (LPS), or proinflammatory cytokines, they would be activated immediately (Davalos et al., 2005). Upon activation, their morphology would change, from small cell body with fine processes to large cell body with amoeboid processes. They also undergo rapid proliferation in order to increase their number for the upcoming battle, demonstrated by upregulation of complement receptor type 3 (OX42) immunostaining (Kim and de Vellis, 2005). Many signals, such as major histocompatibility complex (MHC) antigens, T- and B-lymphocyte markers, and other immune cell antigens, begin to appear on microglia (Wang et al., 2002), which make them as antigen-presenting cells (APCs) (Chavarria and Alcocer-Varela, 2004; Hickey and Kimura, 1988). Besides, microglia migrate to the invaded area (known as chemotaxis), engulf the offending material (phagocytosis), and secrete proinflammatory factors to promote more cells to proliferate. Not only destroy the invading external antigen and remove potential deleterious debris, microglia can also promote tissue repair by secreting growth factors thus facilitate returning to homeostasis (Kreutzberg, 1996). In conclusion, microglia are constantly scanning the brain environment and searching for brain damage to form the first line of defense. Astrocytes are the most frequent cells, constituting more than 50% of cells in CNS. These star-shaped cells have a central cell body, approximately 15–17 μm in diameter, and long processes extending in all directions. Processes extending from different cells establish contacts with each other via gap junctions, thereby forming networks of coupled astrocytes (Blomstrand et al., 1999; Cornell-Bell et al., 1990; Guthrie et al., 1999; Nedergaard et al., 2003). Moreover, their processes envelope synapses formed by neurons and also contact the exterior of capillary vessels. Therefore astrocytes act as bridges among all kinds of cells in CNS, including neurons, oligodendrocytes, microglia, endothelia, and astrocytes themselves. Furthermore, activities of astrocytes are generally thought to mirror the metabolic activity of neurons (Haydon and Carmignoto, 2006), because they regulate concentrations of ions and neurotransmitters around synapses (Verkhratsky and Steinhauser, 2000). Astrocytes play indispensable roles in physiological condition; when there are injuries or trauma, astrocytes often withdraw their arms
and slack off on their stabilizing chores, so their role as neuronal partners would weaken or even disappear. However, they could release neurotrophic factors such as transforming growth factor beta (TGF-β) and nerve growth factor (NGF). These factors are beneficial for the repairment, proliferation and filling up the space to form glial scar replacing the cells that cannot regenerate (Escartin and Bonvento, 2008). This kind of glial scar would hinder axon regeneration to some extent. Another notable characteristic of activated astrocytes is elevated intracellular calcium (Ca2+) (see Fig. 1). By diffusion of inositol triphosphate (IP3) through gap junctions and extracellular adenosine triphosphate (ATP) signaling, astrocytes signal each other in the form of calcium wave, resulting in elevation of Ca2+ level in adjacent cells (Haydon, 2001). Increased Ca 2+ binds to various molecular targets trigger or contribute to intracellular signal transduction pathways, including dependent phospholipases such as phospholipase C (PLC) and phospholipase A2 (PLA2), and downstream calcium dependent elements (such as phosphatases and protein kinases), some of which would result in rapid motility and morphological changes of astrocytes (Scemes, 2000). Additionally, the calcium wave can also propagate to neighboring microglia (Schipke et al., 2002). Microglia are activated earlier than astrocytes Activation of microglia and astrocytes occurs at different stage in several neurodegenerative diseases. In experimental autoimmune encephalomyelitis (EAE), microglia proliferated at the initial stage while astrocytes started to respond markedly at the late recovery stage (Matsumoto et al., 1992). In Alzheimer's disease (AD), activation of astrocytes also occurred subsequent to microglial activation (Gatan and Overmier, 1999). Similarly, astrocytes were activated following microglial activation when human-derived dense-core amyloid plaques (typical for Alzheimer's disease) were injected into rat brain (Frautschy et al., 1998). Trimethyltin (TMT), a triorganotin compound, is employed as a well established neurodegeneration model. In TMT treated rats, significant increases in the expression of glial fibrillary acidic protein (GFAP, a marker for astrocytic activation) typically occurred after microglial activation (McCann et al., 1996). Moreover, it has been reported that microglial responses occurred with TMT concentrations at or below the neurotoxicity limit, whereas astrocytes required a high concentration to be activated (Reali et al., 2005), confirming that microglia respond to TMT more quickly than astrocytes. In neuropathic pain, microglia is also activated earlier than astrocytes. For instance, astrocytes have been reported to respond to spinal nerve
Fig. 1. Schematic picture of calcium wave. ATP and IP3 mediate the propagation of elevated intracellular calcium, which would affect various signaling pathways including PLA2 and PLC pathways. ATP: adenosine triphosphate. IP3: inositol triphosphate; R: receptor; PLA2: phospholipase A2; PLC: phospholipase C.
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injury more slowly than microglia (Colburn et al., 1997). Similarly, intrathecal ATP administration caused spinal microglial activation within 1 day, while astrocytic activation peaked at 1–3 days. Furthermore, minocycline (a microglial inhibitor) attenuated the induction but not the early and late phase of maintenance, while fluorocitrate (a glial metabolic inhibitor) attenuated the induction and the early phase but not the late phase of maintenance (Nakagawa et al., 2007). Considering that fluorocitrate disrupts the function of both astrocytes and microglia while minocycline only targets microglia, it was suspected that microglia was activated earlier than astrocytes. Activated microglia promote astrocytic activation Proinflammatory cytokines, which are closely involved in various diseases (including trauma, ischemia, Alzheimer's disease, epilepsy, and others), play important roles in the facilitation of activated microglia for astrocytic activation (secretion of proinflammatory cytokines from microglia is characteristic of its activation, so most studies have been focusing on them.). Among various cytokines, interleukin-1 (IL-1) is a pivotal mediator, not only because of its fast release in these pathological conditions, but also its ability to upregulate other inflammatory cytokines, such as IL-6 and tumor necrosis factor alpha (TNF-α) (John et al. 2005). Therefore, in this part we mainly concentrated on IL-1 to illustrate the cross talk between activation of microglia and astrocytes. IL-1 which has been reported to be mainly produced by microglia, is closely associated with various diseases (Griffin, 2006). In a model of CNS trauma (corticectomy injury), IL-1 positive cells entirely overlapped with ionized calcium binding adaptor molecule 1 (Iba1, a microglial marker) positive microglia surrounding the lesion site, while GFAP immunoreactive cells were not present, underlying that microglia is the only source for IL-1 (Herx et al., 2000; Herx and Yong, 2001). Increased IL-1 expression has been detected in reactive microglia surrounding amyloid plaques in Alzheimer's disease (Shaftel et al., 2007), moreover, IL-1 receptor antagonist has been demonstrated to be neuroprotective in cerebral ischemia, as deletion of genes encoding for both agonists IL-1α and IL-1β in mice reduced ischemic brain damage by 80% (Boutin et al., 2001). Exogenous administration or over expression of the endogenous IL-1 promotes astrocytic activation, which leads to astrogliosis (John et al., 2004). IL-1 injection into brain resulted in astrocytic activation indicated by GFAP upregulation (Balasingam et al., 1994; Lee et al., 2010), moreover, IL-1 has been shown to induce nuclear hypertrophy and intercellular adhesion molecule-1 (ICAM-1) expression in astrocytes (Albrecht et al., 2002; Kyrkanides et al., 1999). Consistent with these reports, astrocytic activation was delayed in mice lacking IL-1 receptor (Herx et al., 2000). IL-1 mediates neurotoxicity of activated astrocytes. It has been reported that large amounts of NO can be induced from primary human astrocytes, which was totally blocked by IL-1 receptor agonist protein (IRAP) (Chao et al., 1996). Moreover, IL-1 dose-dependently inhibited astrocytic glutamate uptake, resulting in increased level of glutamate which would exert over excitation (Hu et al., 2000; Jing et al., 2010). In addition, free radicals were also released from astrocytes activated by IL1 (Thornton et al., 2006). On the other hand, IL-1 also contributes to the protective role of activated astrocytes. Connexin 43 (Cx43) is the main constitutive protein of gap junction, through which some harmful molecules propagate among astrocytes leading to aggravation of damage. Therefore inhibition of Cx43 in astrocytes is generally considered to be neuroprotective. It has been reported that expression of Cx43 and gap junctional communication among astrocytes were inhibited in microglia astrocytes coculture (Rouach et al., 2002b), this inhibition was mimicked by treating astrocyte cultures with conditional medium harvested from activated microglia, indicating that some substances from microglia mediated the inhibitory effect. IL-1β and TNF-α were identified as the main factors responsible for this conditioned medium-mediated activity (Rouach et al., 2002a). In
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addition, IL-1 upregulated nerve growth factor (NGF) and TGF-β in astrocytes at both gene level and protein level (da Cunha et al., 1993; Jauneau et al., 2006), which would be beneficial for recovery in the CNS. Besides, IL-18 plays important role in activation of microglia/ astrocytes. It has been reported that nerve injury induced a striking increase in IL-18 and IL-18 receptor (R) expressions in the dorsal horn, and IL-18 and IL-18R were upregulated in hyperactive microglia and astrocytes respectively. The functional inhibition of IL-18 signaling pathways not only suppressed injury-induced tactile allodynia, but also decreased the phosphorylation of nuclear factor kappaB in spinal astrocytes and the induction of astroglial markers (Miyoshi et al., 2008). Prostaglandin (PG) D2 also contributes to activation of microglia/ astrocytes. In the genetic demyelination mouse twitcher (a model of human Krabbe's disease), activated microglia expressed hematopoietic PGD synthase (HPGDS) and activated astrocytes expressed the DP1 receptor for PGD2. Cultured microglia actively produced PGD2 by the action of HPGDS, while cultured astrocytes expressed two types of PGD2 receptor (DP1 and DP2) and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. Blockade of the HPGDS/PGD2/DP signaling pathway using HPGDS- or DP1-null twitcher mice or treating with an HPGDS inhibitor, resulted in remarkable suppression of astrogliosis and demyelination (Mohri et al., 2006). Activated astrocytes facilitate distant microglial activation via calcium wave Once astrocytes are activated, the cytosolic Ca 2+ would increase and propagate among astrocytes, which is called calcium wave. Initially it was proposed that propagation of calcium wave within the astrocytic network was conducted by diffusion of second messengers through gap junction (such as IP3). However, calcium waves were not totally abolished in cultured astrocytes derived from Cx43-null mice (Naus et al., 1997; Scemes et al., 1998), nor in astrocytes treated with oleomide and anandamide (drugs that can totally prevent dye- and electrical-coupling) (Guan et al., 1997). In contrast, blocking purinergic receptors with the purinergic receptor (P2R) antagonist suramin totally prevented this spread (Guan et al., 1997; Zanotti and Charles, 1997), so ATP is the mainly responsible messenger (Cotrina et al., 1998). Purinergic receptors are expressed prominently on microglia, therefore it is probable that ATP could mediate astrocytes-to-microglia communication (Honda et al., 2001; Norenberg et al., 1997; Shigemoto-Mogami et al., 2001; Suzuki et al., 2004). Investigations have shown that in response to local injury, the ATP released from astrocytes activates local microglia, indicating that the calcium wave among astrocytes network can also spread to microglia (Davalos et al., 2005; Schipke et al., 2002; Verderio and Matteoli, 2001). ATP induces rapid changes in microglial morphology and migration, so that microglia proliferate and migrate towards injury site quickly (Davalos et al., 2005; Haynes et al., 2006). Formation and shedding of membrane vesicles are important for phagocytosis and secretion. Astrocytes-derived ATP could induce formation of vesicles in nearby microglia facilitating microglial phagocytosis, while ATP-degrading enzyme apyrase and P2X7R antagonists were reported to inhibit this process (Fang et al., 2009). Besides, P2Y12 and P2Y6 receptors expressed on microglia have been reported to be critical for movement and phagocytosis respectively (Koizumi et al., 2007; Sasaki et al., 2003). Moreover, microglia also respond to ATP through triggering potassium currents (Boucsein et al., 2003) and secretion of cytokines (Bianco et al., 2005; Hide et al., 2000) and plasminogen (Hide et al., 2000; Inoue et al., 1998), all of which are closely involved in pathological cascades. By propagated astrocytic calcium waves, the distant microglia could be activated. This is significant, especially in the expansion of infarct volume in focal ischemia and spreading of the pain. Ischemia could evolute to an infarct core which is surrounded by ischemic penumbra (ischemia border zone). Microglia far away from the infarct core was also reported to be activated, even though the tissue showed
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no sign of damage (Lehrmann et al., 1997). The astrocytic Ca 2+ signaling and in particular the ability of astrocytes to propagate longdistance Ca 2+ waves probably contribute to the distant microglial activation (Nedergaard and Dirnagl, 2005). Thereafter, the activated microglia and astrocytes in ischemic penumbra would cause a delayed expansion of the infarct volume if not properly treated. Similarly, pain is recognized not only from the injured location, but also from the region far away from the original wound. It is suspected that calcium waves propagated among activated astrocytes spread to distant areas, and microglia far away from the injured site would be activated subsequently, producing proinflammatory cytokines, which are capable to induce overactivation of pain-transmitting neuronal tracts (Hansson, 2006; Milligan et al., 2003; Watkins and Maier, 2003).
Activated astrocytes can also inhibit microglial activities Activated astrocytes can exert inhibitory effect on microglia. Astrocytes have been reported to decrease the production of NO, reactive oxygen species (ROS) and TNF-α from microglia (von Bernhardi and Eugenín, 2004; Smits et al., 2001; Tichauer et al., 2007). Besides, the ability of microglial phagocytizing and removing senile plaque (SP) was markedly suppressed when cocultured with astrocytes. This suppression appears to be a general phenomenon since microglia in the presence of astrocytes showed reduced capacity to phagocytose latex beads as well (Dewitt et al., 1998). What mediates the effect of activated astrocytes on microglia? Transforming growth factor beta (TGF-β), which is mainly produced by astrocytes (Ramírez et al., 2005), has been reported to reduce microglial activation. It deactivated microglia by downregulating the expression of molecules associated with antigen presentation and production of proinflammatory cytokines, NO and oxygen free radicals (Herrera-Molina and von Bernhardi, 2005). Moreover, TGF-β dramatically diminished the clustering of BV-2 cells (a murine microglial cell line) and attenuated its chemotactic migration towards Aβ aggregates (Huang et al., 2010). Besides, pretreatment with TGF-β attenuated the activation of nucleus factor kappa B (NF-κB) and upregulation of IL-1 mRNA levels, thus reducing production and release of proinflammatory cytokines (Chen and Wahl, 2002; Hu et al., 1999).
Conclusions Based on the above, there are complicated intercommunications between activation of microglia and astrocytes (see Fig. 2). Activated microglia facilitates astrocytic activation; activated astrocytes in turn regulate microglial activities and also promote distant microglial activation. Very importantly, astrocytes play a dual role in CNS inflammatory diseases (pathological conditions related with inflammation have been extensively investigating and reporting), not only having the ability to enhance immune responses and postpone restoration, but also limiting CNS inflammation and being neuroprotective (inhibitory effect on activated microglia). An important question is how these two totally opposite effects coexist. The degree of inflammation is crucial; it has been reported that if the inflammatory stimuli was very strong, astrocytes would be unable to inhibit NO production from microglia (von Bernhardi and Ramirez, 2001; von Bernhardi et al., 2007; von Bernhardi and Eugenín, 2004). Consistently, the duration of stimuli is also relevant for the outcome of astrocytic effect on microglial modulation. For example, stimulation of astrocytes with LPS for up to 24 h resulted in inhibitory modulation of microglia (von Bernhardi and Eugenín, 2004), whereas astrocytes exposed to the same proinflammatory condition for 48 h or longer failed to inhibit activation of microglia (von Bernhardi et al., 2007). However, until now there have been few investigations about the inhibitory effect of activated astrocytes on microglial activities. Also there are few studies exploring the point when activated astrocytes have the ability to inhibit detrimental activities of microglia, which would significantly contribute to inhibit CNS inflammation. Conflict of interest None.
Acknowledgment We would like to thank Julia Kravitz (Institute of Guangzhou University of Chinese Medicine) for the advice on grammar and English usage errors in the paper.
Fig. 2. Schematic picture about the intercommunications between activation of microglia and astrocytes. Activated microglia facilitates astrocytes activation by proinflammatory cytokines such as IL-1. On the other hand, activated astrocytes promote distant microglial activation via calcium wave, while it can also inhibit microglial activities demonstrated by downregulating NO and ROS at the same time. Activation or upregulation; inhibition; calcium wave; ATP: adenosine triphosphate; IL-1: interleukin 1; IL-18: interleukin 1; PGD2: prostaglandin D2; TGF-β: transforming growth factor beta; NO: nitric oxide; ROS: reactive oxygen species; TNF-α: tumor necrosis factor alpha.
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Life Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / l i f e s c i e
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Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system W. Liu a,⁎, Y. Tang b,⁎, J. Feng c a b c
Department of Physiology, College of fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China Department of Neurology, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China Department of Physiology, Zhongshan Medical College, Sun Yat-sen University, Guangzhou, 510080, PR China
a r t i c l e
i n f o
Article history: Received 1 January 2011 Accepted 26 May 2011 Keywords: Astrocyte Microglia Activation Cross talk ATP IL-1 TGF-β
a b s t r a c t Microglia and astrocytes in the central nervous system are now recognized as active participants in various pathological conditions such as trauma, stroke, or chronic neurodegenerative disorders. Their activation is closely related with the development and severity of diseases. Interestingly, activation of microglia and astrocytes occurs with a spatially and temporarily distinct pattern. The present review explores the cross talk in the process of their activation. Microglia, activated earlier than astrocytes, promote astrocytic activation. On the other hand, activated astrocytes not only facilitate activation of distant microglia, but also inhibit microglial activities. Molecules contributing to their intercommunication include interleukin-1 (IL-1), adenosine triphosphate (ATP), and transforming growth factor beta (TGF-β). A better understanding about the cross talk between activation of microglia and astrocytes would be helpful to elucidate the role of glial cells in pathological conditions, which could accelerate the development of treatment for various diseases. © 2011 Elsevier Inc. All rights reserved.
Contents Microglia and astrocytes . . . . . . . . . . . . . . . . . . . . . . . . Microglia are activated earlier than astrocytes . . . . . . . . . . . . . . Activated microglia promote astrocytic activation. . . . . . . . . . . . . Activated astrocytes facilitate distant microglial activation via calcium wave Activated astrocytes can also inhibit microglial activities . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Microglia and astrocytes Glia in the central nervous system (CNS) mainly include microglia, astrocytes and oligodendrocytes. Here we mainly talk about microglia and astrocytes, both of which are activated in pathological conditions. Originally they were merely regarded as structural support for neurons. However, more and more evidence indicates that glial cells
⁎ Corresponding authors at: Department of Physiology, College of fundamental Medical Science, Guangzhou University of Chinese Medicine, University Town of Guangzhou, Panyu District, Guangzhou, 510006, PR China. Tel.: + 86 20 39358028. E-mail address: [email protected] (W. Liu). 0024-3205/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2011.05.011
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are active and responsive to environmental changes (being activated). Generally, activation refers to an enhanced ability of a cell to perform a function beyond that present in basal state. For microglia and astrocytes, their activation is multi-dimensional, that is, they proliferate, phagocytose, and release proinflammatory cytokines or growth factors (Kettenmann and Verkhratsky, 2008). Meantime, the cross talk between activated glial cells and neurons has been becoming the focus for these two decades. Neuron can activate glia via various neurotransmitters or modulators, such as glutamate, fractalkine, nitric oxide (NO) and others (Liu et al., 2006; Verge et al., 2004). Conversely, the activated glial cells affect neuronal function and contribute to the development of various diseases such as neurodegenerative diseases, ischemia, and injury. This happens in the process of clearing bacteria or virus, releasing proinflammatory cytokines and neurotrophic factors,
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and forming glial scars. However, whether there are intercommunications between microglia and astrocytes remain to be elucidated. Microglia, constituting around 10–20% of all glial cells, they are derived from bone marrow precursors and represent the brain's internal immune system, thus being considered as the first line of defense. In physiological condition, microglia are ramified and have highly motile processes, surveiling the microenvironment in CNS (Nimmerjahn et al., 2005). Once there are abnormal substances, such as cell necrosis factors, lipopolysaccharide (LPS), or proinflammatory cytokines, they would be activated immediately (Davalos et al., 2005). Upon activation, their morphology would change, from small cell body with fine processes to large cell body with amoeboid processes. They also undergo rapid proliferation in order to increase their number for the upcoming battle, demonstrated by upregulation of complement receptor type 3 (OX42) immunostaining (Kim and de Vellis, 2005). Many signals, such as major histocompatibility complex (MHC) antigens, T- and B-lymphocyte markers, and other immune cell antigens, begin to appear on microglia (Wang et al., 2002), which make them as antigen-presenting cells (APCs) (Chavarria and Alcocer-Varela, 2004; Hickey and Kimura, 1988). Besides, microglia migrate to the invaded area (known as chemotaxis), engulf the offending material (phagocytosis), and secrete proinflammatory factors to promote more cells to proliferate. Not only destroy the invading external antigen and remove potential deleterious debris, microglia can also promote tissue repair by secreting growth factors thus facilitate returning to homeostasis (Kreutzberg, 1996). In conclusion, microglia are constantly scanning the brain environment and searching for brain damage to form the first line of defense. Astrocytes are the most frequent cells, constituting more than 50% of cells in CNS. These star-shaped cells have a central cell body, approximately 15–17 μm in diameter, and long processes extending in all directions. Processes extending from different cells establish contacts with each other via gap junctions, thereby forming networks of coupled astrocytes (Blomstrand et al., 1999; Cornell-Bell et al., 1990; Guthrie et al., 1999; Nedergaard et al., 2003). Moreover, their processes envelope synapses formed by neurons and also contact the exterior of capillary vessels. Therefore astrocytes act as bridges among all kinds of cells in CNS, including neurons, oligodendrocytes, microglia, endothelia, and astrocytes themselves. Furthermore, activities of astrocytes are generally thought to mirror the metabolic activity of neurons (Haydon and Carmignoto, 2006), because they regulate concentrations of ions and neurotransmitters around synapses (Verkhratsky and Steinhauser, 2000). Astrocytes play indispensable roles in physiological condition; when there are injuries or trauma, astrocytes often withdraw their arms
and slack off on their stabilizing chores, so their role as neuronal partners would weaken or even disappear. However, they could release neurotrophic factors such as transforming growth factor beta (TGF-β) and nerve growth factor (NGF). These factors are beneficial for the repairment, proliferation and filling up the space to form glial scar replacing the cells that cannot regenerate (Escartin and Bonvento, 2008). This kind of glial scar would hinder axon regeneration to some extent. Another notable characteristic of activated astrocytes is elevated intracellular calcium (Ca2+) (see Fig. 1). By diffusion of inositol triphosphate (IP3) through gap junctions and extracellular adenosine triphosphate (ATP) signaling, astrocytes signal each other in the form of calcium wave, resulting in elevation of Ca2+ level in adjacent cells (Haydon, 2001). Increased Ca 2+ binds to various molecular targets trigger or contribute to intracellular signal transduction pathways, including dependent phospholipases such as phospholipase C (PLC) and phospholipase A2 (PLA2), and downstream calcium dependent elements (such as phosphatases and protein kinases), some of which would result in rapid motility and morphological changes of astrocytes (Scemes, 2000). Additionally, the calcium wave can also propagate to neighboring microglia (Schipke et al., 2002). Microglia are activated earlier than astrocytes Activation of microglia and astrocytes occurs at different stage in several neurodegenerative diseases. In experimental autoimmune encephalomyelitis (EAE), microglia proliferated at the initial stage while astrocytes started to respond markedly at the late recovery stage (Matsumoto et al., 1992). In Alzheimer's disease (AD), activation of astrocytes also occurred subsequent to microglial activation (Gatan and Overmier, 1999). Similarly, astrocytes were activated following microglial activation when human-derived dense-core amyloid plaques (typical for Alzheimer's disease) were injected into rat brain (Frautschy et al., 1998). Trimethyltin (TMT), a triorganotin compound, is employed as a well established neurodegeneration model. In TMT treated rats, significant increases in the expression of glial fibrillary acidic protein (GFAP, a marker for astrocytic activation) typically occurred after microglial activation (McCann et al., 1996). Moreover, it has been reported that microglial responses occurred with TMT concentrations at or below the neurotoxicity limit, whereas astrocytes required a high concentration to be activated (Reali et al., 2005), confirming that microglia respond to TMT more quickly than astrocytes. In neuropathic pain, microglia is also activated earlier than astrocytes. For instance, astrocytes have been reported to respond to spinal nerve
Fig. 1. Schematic picture of calcium wave. ATP and IP3 mediate the propagation of elevated intracellular calcium, which would affect various signaling pathways including PLA2 and PLC pathways. ATP: adenosine triphosphate. IP3: inositol triphosphate; R: receptor; PLA2: phospholipase A2; PLC: phospholipase C.
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injury more slowly than microglia (Colburn et al., 1997). Similarly, intrathecal ATP administration caused spinal microglial activation within 1 day, while astrocytic activation peaked at 1–3 days. Furthermore, minocycline (a microglial inhibitor) attenuated the induction but not the early and late phase of maintenance, while fluorocitrate (a glial metabolic inhibitor) attenuated the induction and the early phase but not the late phase of maintenance (Nakagawa et al., 2007). Considering that fluorocitrate disrupts the function of both astrocytes and microglia while minocycline only targets microglia, it was suspected that microglia was activated earlier than astrocytes. Activated microglia promote astrocytic activation Proinflammatory cytokines, which are closely involved in various diseases (including trauma, ischemia, Alzheimer's disease, epilepsy, and others), play important roles in the facilitation of activated microglia for astrocytic activation (secretion of proinflammatory cytokines from microglia is characteristic of its activation, so most studies have been focusing on them.). Among various cytokines, interleukin-1 (IL-1) is a pivotal mediator, not only because of its fast release in these pathological conditions, but also its ability to upregulate other inflammatory cytokines, such as IL-6 and tumor necrosis factor alpha (TNF-α) (John et al. 2005). Therefore, in this part we mainly concentrated on IL-1 to illustrate the cross talk between activation of microglia and astrocytes. IL-1 which has been reported to be mainly produced by microglia, is closely associated with various diseases (Griffin, 2006). In a model of CNS trauma (corticectomy injury), IL-1 positive cells entirely overlapped with ionized calcium binding adaptor molecule 1 (Iba1, a microglial marker) positive microglia surrounding the lesion site, while GFAP immunoreactive cells were not present, underlying that microglia is the only source for IL-1 (Herx et al., 2000; Herx and Yong, 2001). Increased IL-1 expression has been detected in reactive microglia surrounding amyloid plaques in Alzheimer's disease (Shaftel et al., 2007), moreover, IL-1 receptor antagonist has been demonstrated to be neuroprotective in cerebral ischemia, as deletion of genes encoding for both agonists IL-1α and IL-1β in mice reduced ischemic brain damage by 80% (Boutin et al., 2001). Exogenous administration or over expression of the endogenous IL-1 promotes astrocytic activation, which leads to astrogliosis (John et al., 2004). IL-1 injection into brain resulted in astrocytic activation indicated by GFAP upregulation (Balasingam et al., 1994; Lee et al., 2010), moreover, IL-1 has been shown to induce nuclear hypertrophy and intercellular adhesion molecule-1 (ICAM-1) expression in astrocytes (Albrecht et al., 2002; Kyrkanides et al., 1999). Consistent with these reports, astrocytic activation was delayed in mice lacking IL-1 receptor (Herx et al., 2000). IL-1 mediates neurotoxicity of activated astrocytes. It has been reported that large amounts of NO can be induced from primary human astrocytes, which was totally blocked by IL-1 receptor agonist protein (IRAP) (Chao et al., 1996). Moreover, IL-1 dose-dependently inhibited astrocytic glutamate uptake, resulting in increased level of glutamate which would exert over excitation (Hu et al., 2000; Jing et al., 2010). In addition, free radicals were also released from astrocytes activated by IL1 (Thornton et al., 2006). On the other hand, IL-1 also contributes to the protective role of activated astrocytes. Connexin 43 (Cx43) is the main constitutive protein of gap junction, through which some harmful molecules propagate among astrocytes leading to aggravation of damage. Therefore inhibition of Cx43 in astrocytes is generally considered to be neuroprotective. It has been reported that expression of Cx43 and gap junctional communication among astrocytes were inhibited in microglia astrocytes coculture (Rouach et al., 2002b), this inhibition was mimicked by treating astrocyte cultures with conditional medium harvested from activated microglia, indicating that some substances from microglia mediated the inhibitory effect. IL-1β and TNF-α were identified as the main factors responsible for this conditioned medium-mediated activity (Rouach et al., 2002a). In
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addition, IL-1 upregulated nerve growth factor (NGF) and TGF-β in astrocytes at both gene level and protein level (da Cunha et al., 1993; Jauneau et al., 2006), which would be beneficial for recovery in the CNS. Besides, IL-18 plays important role in activation of microglia/ astrocytes. It has been reported that nerve injury induced a striking increase in IL-18 and IL-18 receptor (R) expressions in the dorsal horn, and IL-18 and IL-18R were upregulated in hyperactive microglia and astrocytes respectively. The functional inhibition of IL-18 signaling pathways not only suppressed injury-induced tactile allodynia, but also decreased the phosphorylation of nuclear factor kappaB in spinal astrocytes and the induction of astroglial markers (Miyoshi et al., 2008). Prostaglandin (PG) D2 also contributes to activation of microglia/ astrocytes. In the genetic demyelination mouse twitcher (a model of human Krabbe's disease), activated microglia expressed hematopoietic PGD synthase (HPGDS) and activated astrocytes expressed the DP1 receptor for PGD2. Cultured microglia actively produced PGD2 by the action of HPGDS, while cultured astrocytes expressed two types of PGD2 receptor (DP1 and DP2) and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. Blockade of the HPGDS/PGD2/DP signaling pathway using HPGDS- or DP1-null twitcher mice or treating with an HPGDS inhibitor, resulted in remarkable suppression of astrogliosis and demyelination (Mohri et al., 2006). Activated astrocytes facilitate distant microglial activation via calcium wave Once astrocytes are activated, the cytosolic Ca 2+ would increase and propagate among astrocytes, which is called calcium wave. Initially it was proposed that propagation of calcium wave within the astrocytic network was conducted by diffusion of second messengers through gap junction (such as IP3). However, calcium waves were not totally abolished in cultured astrocytes derived from Cx43-null mice (Naus et al., 1997; Scemes et al., 1998), nor in astrocytes treated with oleomide and anandamide (drugs that can totally prevent dye- and electrical-coupling) (Guan et al., 1997). In contrast, blocking purinergic receptors with the purinergic receptor (P2R) antagonist suramin totally prevented this spread (Guan et al., 1997; Zanotti and Charles, 1997), so ATP is the mainly responsible messenger (Cotrina et al., 1998). Purinergic receptors are expressed prominently on microglia, therefore it is probable that ATP could mediate astrocytes-to-microglia communication (Honda et al., 2001; Norenberg et al., 1997; Shigemoto-Mogami et al., 2001; Suzuki et al., 2004). Investigations have shown that in response to local injury, the ATP released from astrocytes activates local microglia, indicating that the calcium wave among astrocytes network can also spread to microglia (Davalos et al., 2005; Schipke et al., 2002; Verderio and Matteoli, 2001). ATP induces rapid changes in microglial morphology and migration, so that microglia proliferate and migrate towards injury site quickly (Davalos et al., 2005; Haynes et al., 2006). Formation and shedding of membrane vesicles are important for phagocytosis and secretion. Astrocytes-derived ATP could induce formation of vesicles in nearby microglia facilitating microglial phagocytosis, while ATP-degrading enzyme apyrase and P2X7R antagonists were reported to inhibit this process (Fang et al., 2009). Besides, P2Y12 and P2Y6 receptors expressed on microglia have been reported to be critical for movement and phagocytosis respectively (Koizumi et al., 2007; Sasaki et al., 2003). Moreover, microglia also respond to ATP through triggering potassium currents (Boucsein et al., 2003) and secretion of cytokines (Bianco et al., 2005; Hide et al., 2000) and plasminogen (Hide et al., 2000; Inoue et al., 1998), all of which are closely involved in pathological cascades. By propagated astrocytic calcium waves, the distant microglia could be activated. This is significant, especially in the expansion of infarct volume in focal ischemia and spreading of the pain. Ischemia could evolute to an infarct core which is surrounded by ischemic penumbra (ischemia border zone). Microglia far away from the infarct core was also reported to be activated, even though the tissue showed
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no sign of damage (Lehrmann et al., 1997). The astrocytic Ca 2+ signaling and in particular the ability of astrocytes to propagate longdistance Ca 2+ waves probably contribute to the distant microglial activation (Nedergaard and Dirnagl, 2005). Thereafter, the activated microglia and astrocytes in ischemic penumbra would cause a delayed expansion of the infarct volume if not properly treated. Similarly, pain is recognized not only from the injured location, but also from the region far away from the original wound. It is suspected that calcium waves propagated among activated astrocytes spread to distant areas, and microglia far away from the injured site would be activated subsequently, producing proinflammatory cytokines, which are capable to induce overactivation of pain-transmitting neuronal tracts (Hansson, 2006; Milligan et al., 2003; Watkins and Maier, 2003).
Activated astrocytes can also inhibit microglial activities Activated astrocytes can exert inhibitory effect on microglia. Astrocytes have been reported to decrease the production of NO, reactive oxygen species (ROS) and TNF-α from microglia (von Bernhardi and Eugenín, 2004; Smits et al., 2001; Tichauer et al., 2007). Besides, the ability of microglial phagocytizing and removing senile plaque (SP) was markedly suppressed when cocultured with astrocytes. This suppression appears to be a general phenomenon since microglia in the presence of astrocytes showed reduced capacity to phagocytose latex beads as well (Dewitt et al., 1998). What mediates the effect of activated astrocytes on microglia? Transforming growth factor beta (TGF-β), which is mainly produced by astrocytes (Ramírez et al., 2005), has been reported to reduce microglial activation. It deactivated microglia by downregulating the expression of molecules associated with antigen presentation and production of proinflammatory cytokines, NO and oxygen free radicals (Herrera-Molina and von Bernhardi, 2005). Moreover, TGF-β dramatically diminished the clustering of BV-2 cells (a murine microglial cell line) and attenuated its chemotactic migration towards Aβ aggregates (Huang et al., 2010). Besides, pretreatment with TGF-β attenuated the activation of nucleus factor kappa B (NF-κB) and upregulation of IL-1 mRNA levels, thus reducing production and release of proinflammatory cytokines (Chen and Wahl, 2002; Hu et al., 1999).
Conclusions Based on the above, there are complicated intercommunications between activation of microglia and astrocytes (see Fig. 2). Activated microglia facilitates astrocytic activation; activated astrocytes in turn regulate microglial activities and also promote distant microglial activation. Very importantly, astrocytes play a dual role in CNS inflammatory diseases (pathological conditions related with inflammation have been extensively investigating and reporting), not only having the ability to enhance immune responses and postpone restoration, but also limiting CNS inflammation and being neuroprotective (inhibitory effect on activated microglia). An important question is how these two totally opposite effects coexist. The degree of inflammation is crucial; it has been reported that if the inflammatory stimuli was very strong, astrocytes would be unable to inhibit NO production from microglia (von Bernhardi and Ramirez, 2001; von Bernhardi et al., 2007; von Bernhardi and Eugenín, 2004). Consistently, the duration of stimuli is also relevant for the outcome of astrocytic effect on microglial modulation. For example, stimulation of astrocytes with LPS for up to 24 h resulted in inhibitory modulation of microglia (von Bernhardi and Eugenín, 2004), whereas astrocytes exposed to the same proinflammatory condition for 48 h or longer failed to inhibit activation of microglia (von Bernhardi et al., 2007). However, until now there have been few investigations about the inhibitory effect of activated astrocytes on microglial activities. Also there are few studies exploring the point when activated astrocytes have the ability to inhibit detrimental activities of microglia, which would significantly contribute to inhibit CNS inflammation. Conflict of interest None.
Acknowledgment We would like to thank Julia Kravitz (Institute of Guangzhou University of Chinese Medicine) for the advice on grammar and English usage errors in the paper.
Fig. 2. Schematic picture about the intercommunications between activation of microglia and astrocytes. Activated microglia facilitates astrocytes activation by proinflammatory cytokines such as IL-1. On the other hand, activated astrocytes promote distant microglial activation via calcium wave, while it can also inhibit microglial activities demonstrated by downregulating NO and ROS at the same time. Activation or upregulation; inhibition; calcium wave; ATP: adenosine triphosphate; IL-1: interleukin 1; IL-18: interleukin 1; PGD2: prostaglandin D2; TGF-β: transforming growth factor beta; NO: nitric oxide; ROS: reactive oxygen species; TNF-α: tumor necrosis factor alpha.
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