[Frontiers in Bioscience S3, 869-883, June 1, 2011]

Microglia-friend or foe

Hui Zhang1,2, Fu-Wu Wang1,2, lin-Li Yao1,2, Ai-Jun Hao1,2

1Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Jinan, Shandong, 250012, PR China, 2Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Jinan, Shandong, 250012, PR China

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Multi-faceted functions of activated microglia in CNS inflammation, neurogenesis and brain tumor
3.1. Microglia in neuroinflammation
3.1.1. Neuroprotective microglia
3.1.1.1. Neurotrophic factors
3.1.1.2. Anti-inflammatory factor
3.1.1.3. Microglial motility and phagocytosis
3.1.2. Neurotoxic microglia
3.1.2.1. Pro-inflammatory cytokines
3.1.2.2. Reactive oxygen and nitrogen species
3.1.2.3. Glutamate
3.2. Microglia in neurogenesis
3.2.1. Proinflammatory cytokines and their dual role in neurogenesis
3.2.1.1. IL-6 and its dual role in neurogenesis
3.2.1.2. TNF-a and its dual role in neurogenesis
3.2.1.3. IL-1b and its dual role in neurogenesis
3.2.1.4. IFN-g and its dual role in neurogenesis
3.2.2. Nitric oxide and its dual role in neurogenesis
3.2.3. Effect of chemokines and chemokine receptors on the neurogenesis
3.3. Microglia in brain tumor
3.3.1. Anti-tumor activity
3.3.2. Pro-tumor activity
3.3.3. Therapeutic potential of microglia activation in brain tumor
4. Conclusion
5. Acknowledgments
6. Reference

1. ABSTRACT

Microglia, as the immune effectors in the central nervous system, respond to pathological conditions and participate in the initiation and progression of neurological disorders such as inflammation and brain tumor by releasing potential neurotrophic or cytotoxic molecules, presenting the antigen to T cell and interacting with brain tumor. Evidences also suggest that microglia are capable of promoting or inhibiting the proliferation and differentiation of neural stem cells by secreting series of biologically active molecules. In this review, we focus on three aspects-inflammation, neurogensis and brain tumor to illustrate the multi-faceted activities of microglia in the normal and pathologic brain.

2. INTRODUCTION

In recent years, the glial cells, especial microglial functional phenotype causes great interest. Microglia comprise 10-20% of all glial cells in the central nervous system (CNS) and make up the main cellular component of CNS (1 ). Although the origin of microglia has been debated for many years, current data indicate that they are of mesenchymal origin and invade the brain during development. So, microglia have the functions similar to those of other tissue macrophages, including phagocytosis, production of a plethora of bioactive molecules and antigen presentation (2 ).

In the physiological conditions, microglia display a "quiescent" phenotype, also called "surveying" state. On insult to brain, microglia become markedly activated and produce a great deal of molecules. It was reported that activated microglia can release series of inflammatory chemical substances such as interleukin-1(IL-1), interleukin-6(IL-6), tumor necrosis factor-α� (TNF-α), and Nitric-Oxide Synthase (NOS) (3), which enhance the inflammatory response in and around the injuried sites, promote the neuronal death and inhibit the neuronal maturation and differentiation. Besides, activated microglia produce many kinds of neurotrophic factors, growth factors and anti-inflammatory factors such as brain-derived neurotrophic factor(BDNF), glial cell-derived neurotrophic factor (GDNF), and transforming growth factor-β(TGF-β)(4-5). And the factors can downregulate the inflammatory response, protect the neuron from injury and promote the neurogenesis. In addition, microglia also can modulate the migration, survival, and proliferation of brain tumor cells via different mechanisms by secreting lots of relative molecules (6). The findings above suggest that the activated microglia may function as a double edged sword in the CNS. In this review, we focus on the dual action of microglia in CNS inflammation, neurogenesis and brain tumor in the intact and injured brain.

3. MULTI-FACETED FUNCTIONS OF ACTIVATED MICROGLIA IN CNS INFLAMMATION, NEUROGENESIS AND BRAIN TUMOR

3.1 Microglia in neuroinflammation

Any injury or insult to the brain including ischemia, stroke, trauma and neurodegenetive diseases will elicit an obviuos neuroinflammatory response in the CNS, and the neuroinflammatory diseases are calling for more attentions beause of the high morbidity nowsdays. With an enhanced understanding about the pathological process, it was reported that microglia, as the resident immune cells in the CNS, play a critical role in the inflammation of CNS. Their engagement can become either neuroprotective or neurotoxic, leading to amelioration or aggravation of disease progression. For one thing, activation enables microglia to maintain and support neuronal survival (7-8) by releasing neurotrophic factors, anti-inflammatory molecules and clearing toxic products or invading pathogens. For another, overactivated microglia can be neurotoxic by releasing pro-inflammatory factors(9), cytotoxic substances such as reactive oxygen and nitrogen species (10) and glutamate(Figure 1).

3.1.1 .Neuroprotective microglia

Activated microglia can involve in neuron protection by blocking proinflammatory response and producing high levels of neurotrophic factors (NTFs) and anti-inflammatory cytokines together with enhanced phagocytic activity.

3.1.1.1. Neurotrophic factors

Microglia can produce NTFs to support neuronal survival and growth (11-12) . NTFs, such as nerve growth factor (NGF), BDNF, GDNF and insulin-like growth factor-1(IGF-1), play important roles in functional maintenance, axons growth, synaptic transmission and plasticity (13) and neuronal survival (14) in the pathological state. Besides their classical effects, NTFs can also inhibit the inflammation (15-16). Based on their effects, NTFs are protective in neuroinflammatory diseases. For example, NGF can attenuate deterioration of AD by reducing oxidant-induced beta-amyloid neurotoxicity in sporadic Alzheimer's disease cybrids (17) and inhibiting the amyloidogenic processing of amyloid precursor protein (APP), which is among the first hypothesized primary trigger of AD pathogenesis.(18 ). BDNF has been demonstrated to be positive in AD (19), stoke(20) and others. GDNF is also beneficial for the survival of dopaminergic neurons (21). Additionally, IGF-I can promote neuronal survival by blocking apoptosis, even play an essential role in Purkinje neuron survival at birth (22). What's more, IGF-1 protect the developing oligodendrocytes from glutamate toxicity In vitro (23 ) and IGF-1 treatment attenuated the damage to oligodendrocyte progenitors in hypoxic-ischemic injury in neonatal rats (24).

3.1.1.2. Anti-inflammatory factor

Activated microglia can protect neurons by producing antiinflammatory cytokines . Here, interleukin-10(IL-10) and TGFβ1 will be discussed. Microglia can both produce and respond to IL-10(25) . Studies show that IL-10 plays an essential role in mediating the inflammatory processes and cell survival in brain by inhibiting the production of proinflammatory cytokines (26). In addition, it was reported that in many models of CNS injury, administration of IL-10 can also suppress the morphological alterations associated with glial activation (26-27), enzymes involved in the generation of inflammatory mediators and oxygen-free radicals (28-29), leukocyte infiltration (30) and the production of A chemokines (31). Further more, IL-10 can directly increase the survival of neurons (32 33 ), astrocytes (34 ), oligodendrocytes (28) and microglia ( 35 ). TGF-β1, which is highly expressed in several models of CNS pathology, has multiple roles including modulating inflammation and neuronal survival(36-37). It has been shown that TGF-β1 knockout mice develop spontaneous neurodegeneration(38-39). TGF-β1 can directly downregulate the expression of other proinflammatory cytokines and is involved in the resolution of inflammation (40) in diseases such as periventricular white matter damage(41-42). In the AD model, neuroprotective effects of TGF-β1 may contribute to both directly promoting the neuronal survival and enhancing the Aβ uptaking (43). TGFβ1 can elicits the expression of Fas-associated death domainlike interleukin 1β-converting enzyme(FLICE)-inhibitor protein in microglia through a MAPK kinase-dependent pathway and inhibits Fas-mediated apoptosis of microglia (44).

3.1.1.3. Microglial motility and phagocytosis

In the neuroinflammatory diseases, microglia are obviously activated, rapidly extend their processes and migrate to the lesion sites or toward damaged neurons to act more locally in the killing of microbes or clearing the debris (45). Chemokine receptors and Integrin-associated receptor complexes play important roles in the process. Chemokine receptors are the major class of receptors for triggering directed migration of microglia, including CXCR3(46), CX3CR1(47), CCR2 and others. Integrin-associated receptor complexes, containing the macrophage antigen complex-1 (Mac-1), receptor CD11a/CD18, leukocyte common antigen 1 (LFA-1)(48) and all β2-integrin receptor complexes and others also function importantly in guiding the migration of microglia to the destination. Microglial phagocytosis could be divided into two distinct responses: a pro-inflammatory cascade which is induced by phagocytosis of pathogens and stimulation of toll-like receptors (TLRs); anti-inflammatory response which is induced by clearance of apoptotic cell membranes and recognition of phosphatidylserine (PtdSer) residues(49). Microglia express distinct types of receptors such as scavenger receptors and complement binding receptors, which take part in the phagocytosis of apoptotic neurons, uptaking of denatured or modified proteins and lipoproteins (50) or the clearance of neuronal structures predetermined to die.

The protective role of phagocytosis are proved in many inflammatory diseases. In AD, microglia play critical roles in the uptake and proteolytic clearance of both soluble and fibrillary forms of amyloid-beta protein (51). In ischemia/reperfusion (I/R) models, microglia may appear at the time of apoptotic neuronal death, and participate in phagocytic action in the CA1 region(52).

3.1.2. Neurotoxic microglia

Besides the protective effects, microglia have been shown to attack damaged neurons by secreting a variety of neurotoxic factors including inflammatory cytokines, reactive oxygen species, NO and glutamate, thus complicate the pathogenesis of neuroinflammatory diseases.

3.1.2.1. Pro-inflammatory cytokines

Over or prolonged production of cytokines by microglia may lead to more neurotoxicity. During a disruption of CNS homeostasis, microglia can produce as well as respond to a multitude of inflammatory cytokines such as TNF-a, IL-1, IL-6, IL-2 and interferon-γ (IFN-γ) (53).

The knockout mice showed significant reductions in the number of dying hippocampal neurons after ischemia because of lacking TNF-a and IL-1 (54). TNF-α is complicated in the pathogenesis of CNS inflammatory diseases. Although TNF-α at lower levels is associated with a neuroprotective effect, this cytokine appears to induce neurodegeneration at high level. The actions of TNF-a are mediated through two membrane receptors, TNF-receptor-1 (TNF-R1) and TNF-R2(55). The activation of TNF-R1 leads to cell apoptosis (56) whereas TNF-R2 promotes cell growth and proliferation (57). Aberrant TNF-a/TNF-R1 signaling can have a potentially major role in the CNS pathologies such as in hypoxic rats and the pathology can cause oligodendrocyte death and demyelination(58). IL-1 appears to be involved in the processes of leading to neuronal death, and inhibition of this cytokine block the effects (59). The actions of IL-1β (the major soluble form of IL-1) are accomplished via the type I receptor (60). A significant increase in IL-1β production by microglial cells and expression of IL-1R1 on oligodendrocytes in PWM of neonatal brain was observed following hypoxic injury (61). IL-1β can delay the white matter development and recovery in hypoxic conditions via block oligodendrocyte proliferation at the late progenitor/pro-oligodendrocyte stage (52,62) and involved in transcriptional activation of iNOS gene and NO generation (55).

>3.1.2.2. Reactive oxygen and nitrogen species

Reactive oxygen and nitrogen species are significant factors in microglial-driven inflammation(63). Excess production of ROS and reactive nitrogen species (RNS) has been described to damage immature oligodendrocytes (64). Of these reactive oxygen and nitrogen species, nitric oxide (NO) is most studied . NO is synthesized by the enzyme nitric oxide synthase (NOS) from Larginine (52). Three isoforms of NOS are known to exist: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). In the damaged brain iNOS is induced mainly in microglia and astrocytes by pathogens, damage or hypoxia (65-67). Although low concentrations inhibit apoptosis, excessive production of NO can lead to neuronal damage and toxicity to the immature oligodendrocytes resulting in their death and delayed myelination in hypoxic injury (67). High levels of NO induce RONS, which cause oxidative/nitrosative stress to cells, in turn activating the mitochondrial pathway of apoptosis.

3.1.2.3. Glutamate

Glutamate, a major excitatory transmitter in the CNS, can turn excitotoxicity under various neurological disorders, including inflammation, ischemia and neurodegenerative diseases (68-69). Previous studies have demonstrated that activated microglia release a large amount of glutamate leading to neuronal damage (70-72), and then the released glutamate activates microglia in an autocrine/paracrine manner(11). In fact, activated microglia act as an executioner to determine neuronal and glial survival. Glutamate not only can directly induce neuronal death through NMDA receptor signaling(72), but also can affect the neuronal apoptosis directly by altering the release of proinflammatory cytokines, neurotrophic factors and growth factors such as TNF-a, IL-1β and IGF-1 produced by microglia under hypoxic conditions (24).

Efficient reuptake of released glutamate is essential for preventing glutamate receptor overstimulation and neuronal and glial death. High-affinity Na+-dependent glutamate transporters, also called excitatory amino acid transporters (EAATs), are responsible for this(73-74). Five different types of glutamate transporters are distributed in neuron and glia in the mature CNS (74-75). Although microglia may serve as a back-up system by expressing glutamate receptors and transporters, they did not prevent excito-neurotoxicity with the uptake of extracellular glutamate via EAATs as astrocytes did (72). In vitro studies have also shown that activated microglia block glutamate transporters in oligodendrocytes, resulting in extracellular glutamate accumulation and the subsequent oligodendrocyte death. And AMPA/kainate mechanism may contribute to altering glutamate homeostasis during the process (76). However, whether activated microglia also downregulate or dysregulate astrocytic EAATs, then contribute to neurodegeneration in neurological diseases need to be elucidated .

3.2. Microglia in neurogenesis

Although it is well known that neural stem cells (NSCs) in adult mammal brain (77-78) can continuously produce new neurons throughout life to replace dying neurons and contribute to specific functions, the exact regulatory mechanisms are largely unknown. In addition to intrinsic properties, NSCs proliferation and differentiation are regulated by the characteristics of the microenvironment or niche in which they reside (79-80). Recently, microglia, as well as astrocytes have been regarded as the component of the CNS microenvironment and play important roles in the neurogenesis (81-82).

It was reported that in normal conditions, microglia display a quiescent phenotype and secret several neurotrophic factors, as well as some cytokines and chemokines (8), which are involved in modulating the cell behavior of NSCs (83). Under pathological circumstance, microglia, as one of the first cell types in brain to respond to injury or insult, become significantly activated and express series of bioactive factors such as proinflammatory cytokines, free radicals, chemokines, and neurotrophic factors (84-85). Generous evidence demonstrate that it was the soluble bioactive molecules produced by activated microglia that participated in modulating the behaviors of NSCs (86-87). Although initial studies show that microglia activation can be detrimental for adult neurogenesis, recent findings indicate that microglia under certain circumstances can be beneficial and support the neurogenesis. Here we summarize the current knowledge about microglia in the neurogenesis by discussing the dual action of molecules secreted from microglia (Figure 2).

3.2.1. Proinflammatory cytokines and their dual role in neurogenesis

It is well known that any injury or insult, ranging from hypoxia, ischemia, infection to neurodegenetive disease, would elicit a characteristic neuroinflammatory reaction in the CNS. Microglia, as the key player mediating this response, secret a series of pro- and anti-inflammatory molecules. Among the various molecules, we mainly discussed the following proinflammatory cytokines.

3.2.1.1. IL-6 and its dual role in neurogenesis

IL-6, as a pleiotropic inflammatory cytokine, is overexpressed by activated microglia once insult. An in vitro study showed that the neuronal differentiation of hippocampal neural progenitor cells (NPCs) expressing the IL-6 receptor significantly decreased by approximately 50% when exposed to recombinant IL-6 cytokine, while the gliogenesis (astrocytic and oligodendrocytic differentiation) was unaffected. Addition of neutralizing anti-IL-6 antibody to microglial conditioned medium fully restored the in vitro neurogenesis (86). This implies that IL-6 serves as a key inhibitor of neurogenesis (88). However, several studies showed that IL-6 released by activated microglia promote astrocytic differentiation of NSPCs via the activation of the Janus kinase ⁄ signal transducer and activation of transcription (JAK ⁄ STAT) and mitogen-activated protein kinase (MAPK) pathways (89-90). Besides, IL-6 induces the proliferation of adult spinal cord-derived neural progenitors via the JAK2/STAT3 pathway with EGF-induced MAPK phosphorylation (91). The data above suggest that the IL-6 plays important and complex roles in modulating the cell behaviors of NSCs via different signaling pathways.

3.2.1.2. TNF-a and its dual role in neurogenesis

TNF-a, another common proinflammatory cytokine, is up-regulated by microglia in most injuried responses and neurodegenerative diseases, and functions by interacting with its receptors, TNF-R1 or TNF-R2. It was reported that TNF-a causes the death of hippocampal NPCs in vitro and markedly reduces their proliferation in a dose-dependent manner (92). In addition, recombinant TNF-a (20ng/ml) was reported to suppress the neurogenesis of NPCs by about 50% (86). Other studies also showed the detrimental effects of TNF-a from LPS-activated microglia on the neurogenesis and cell survival (93). In contrast, several studies showed that TNF-a increased the proliferation of neurospheres from SVZ via IKK/NF-k B signaling, and in vivo findings also illustrated its mitogenic role (94-95). TNF-a also enhances stroke-induced neurogenesis, indicating a possible neuroprotective role (96). Furthermore, Iosif reported that the cell proliferation and generation of new hippocampal neurons significantly increased in both normal and status epilepticus brain of TNF-R1(-/-) and TNF-R1/R2(-/-) mice. However, these was no significant alteration in TNF-R2(-/-) mice under both normal and pathological conditions (97). This implies that TNF-a plays conflicting roles in regulating the differentiation of NSCs acting via different TNF-a receptors.

3.2.1.3. IL-1b and its dual role in neurogenesis

IL-1b , another potent proinflammatory cytokine secreted by activated microglia, its function on neurogenesis was also extensively investigated. Koo found that administration of IL-1b or activation of IL-1 receptor(IL-1R) suppressed hippocampal cell proliferation via the NF-k B signaling pathway. And specific IL-1RI inhibitor or IL-1RI null mice demonstrated the antineurogenic effect (98), which is consistent with the findings that intrahippocampal transplantation of transgenic NPCs overexpressing IL-1R antagonist blocks chronic isolation-induced impairment in neurogenesis (99). However, several studies showed that exposure of NSCs to recombinant IL-1b or neutralization of IL-1b in the conditioned medium from LPS-activated microglia does not exert significant effects on hippocampal neurogenesis (86,93). In addition, it was reported that addition of IL-1b or blocking IL-1R inhibited the astrocytic differentiation, and the effect of IL-1b on NPCs proliferation and differentiation appeared to be mediated by SAPK/JNK, but not ERK, P38MAPK nor NF-k B pathways (100). Taken together, the complex of IL-1b in function and mechanism need to be further explored.

3.2.1.4 IFN-g and its dual role in neurogenesis

Previous studies showed that IFN-g inhibited cell proliferation of newborn rat striatal NPCs sphere, increased cell apoptosis and promoted outward migration of cells from spheres without influencing the differentiation of NPCs in vitro (101). This indicates the detrimental effect of IFN-g on NSPC survival and proliferation (102). In addition, Monje showed that recombinant IFN-g cytokine did not dramatically affect the neurogenesis (86). However, recent studies have demonstrated that microglia treated with low levels of IFN-g promote the neurogenesis (103), and IFN-g can directly increases the neurogenesis of NSCs (104-105). Johansson further demonstrated that IFN-g increased the neuronal yield threefold in striatal NSPC cultures and enhanced the number of oligodendrocytes twofold in hippocampal NSPC cultures (106). Moreover, several studies showed that the effects of IFN-g promoting the neuronal differentiation of NSCs is mediated by the JNK pathway without affecting activities of ERKs 1 and 2 (107). And the proliferation and differentiation of NSC in adult dentate gyrus was markedly increased in IFN-g transgenic mice (108). It was supposed that the neurotoxic and neuroprotective effect of IFN-g could be due to its occurrence in high and low concentrations or to the presence of other bioactive mediators such as LPS or TNF-a (108-109).

3.2.2. Nitric oxide and its dual role in neurogenesis

NO is synthesized by the enzyme NOS in activated microglia and modulate the neurogenesis positively or negatively. It was demonstrated that NO produced by the nNOS inhibits the proliferation and differentiation of NSCs in the SVZ (110-112). And inhibition of nNOS using its selective inhibitor 7-nitroindazole (7-NI) significantly promotes the cell proliferation in the SVZ, rostral migratory stream and olfactory bulb (111). In contrast, NO secreted by iNOS in dentate gyrus and by eNOS in the SVZ promotes neurogenesis after focal ischemia (113-114). Recent finding showed that in rat hippocampus after transient ischemia induced by middle cerebral artery occlusion, the number of nNOS-IR interneurons were significantly decreased, meanwhile, iNOS-IR interneurons appeared and increased (115). In addition, Arora reported that NO inhibits neurogenesis independent of cGMP in dorsal root ganglion, while Koriyama showed that the NO-cGMP signaling promotes the axonal elongation during optic nerve regeneration in the goldfish in vitro and in vivo(116-117). Comprehensively, the effect of NO on the cell survival, proliferation and differentiation varies and different NO synthases play distinct roles in regulating the effect on neurogenesis (118-119).

3.2.3. Effect of chemokines and chemokine receptors on the neurogenesis

Chemokines are small,secreted protein by activated microglia after insult and can modulate the neurogenesis by acting through their chemokine receptors (120). Belmadani reported that in mouse embryos, chemokine receptor CXCR4 was expressed in neural crest cells migrating from the dorsal neural tube and dorsal root ganglia, while chemokines SDF-1 was expressed along the path taken by crest cells to the dorsal root ganglia, suggesting SDF-1/CXCR4 signaling participates in their migration (121). In addition, SDF-1 not only promotes the survival and quiescence of neural progenitor cells (122), but also induces the persistent production of neurons from adult brain stem cells during recovery after stroke by activating the CXCR4 receptor expressed in NSPCs (123 -124). And in cases of CNS damages, SDF-1 can regulate the migration of NSPCs to the damaged sites acting through CXCR4 (125-126), thus promoting the neurogenesis following any insult. Besides, Tran found that human immunodeficiency virus causes direct death of the dentate granule neurons via CXCR4/CCR5 expressed on these cells, and the binding of viral protein gp120 to CXCR4 prevents SDF-1 to initiate its CXCR4-mediated signaling in NSPCs (127). However, the chemokines also recruit the resident microglia and peripheral macrophages to the injuried sites, resulting in uncontrolled inflammatory response and inhibit the neurogenesis (128).

In addition, activated microglia also produce a great deal of anti-inflammatory factors, reactive oxygen species, neurotrophic factors and growth factors such as TGF-b (5), ROS(129), BDNF, GNDF(4) and IGF-1(130). And these molecules have been already demonstrated to be involved and play important roles in modulating the neurogenesis.

It was reported that there are several subpopulations of parenchymal CNS microglia (131-132), which may explain the functional diversity of microglia in modulating the neurogenesis even if both populations were supportive (7,87). In future, the studies exploring the effects of microglia on neurogenesis should focus on the different activated states or short- and long-term influence of microglia on the cell behaviors of NSPCs and survival of new neurons, as well as its possible molecular mechanism.

3.3. Microglia in brain tumor

Besides the important roles in inflammation and neurogenesis, the presence of microglia in brain tumor has also been paid much attention. As the development of immunohistochemistry, the detailed descriptions of the infiltrating macrophage and microglia in brain tumor were demonstrated (133-135). Previously, it was proposed that microglia may play a role in anti-tumorigenesis and induce tumor necrosis. However, recent evidences suggest that microglia suppress immune response and promote tumor progression(136-138;Figure 3).

3.3.1. Anti-tumor activity

The most effective mechanism against tumor cells is antigen-specific cytotoxicity through major histocompatability complex (MHC). Microglia, as one of antigen-presenting cells, present tumor-associated antigens through their MHC class II molecules with the presence of costimulatory molecules (i.e., B7.1, B7.2, CD40, CD80) (6). Microglia obtained from newborn rodent can upregulate MHC class II and adhesion/costimulatory molecules, process antigen and activate T cells. In human glioma microglia express MHC class II and B7.1 and B7.2 costimulatory molecules, indicating that microglia may be capable of presenting antigen in vivo (139). However, tumor cells may aberrantly express MHC class II in the absence of the B7costimulator(139). Recently, reports supported that the antigen presentation function of microglia against glioma is limited (140). MHC molecules are generally restricted to microglia in low levels, when in high concentration ,T-cell activation and proliferation was not induced.

Another cytotoxic effector function of microglia is the generation of superoxide anions. In rat glioma microglia is more dependent on NO than ROS for exerting effector function(141). Microglia releases iNOS in astrocytoma by IL-1β production probably using p38 MAPK and NF-κB signaling pathway (142). However, cytotoxic molecules, such as NO and ROS can also induce the death of immune effector cells. STAT-1 and STAT-3 increase in NF-κB DNA binding and transcriptional activations in microglia (143). It was found that Fas and its ligand FasL was expressed in microglia and G26 glioma, respectively, and leukocyte propagation increase more than three folds when FasL is inhibited (144).This implies that microglia may induce the death of tumor cells by the Fas/FasL signaling.

3.3.2. Pro-tumor activity

Although, previous studies showed that microglia are capable of presenting antigen to T cells in vivo, several studies demonstrated that the antigen presentation function of microglia against glioma is significantly suppressed (140). Increasing studies showed that not only microglia, but glioma also secrete chemoattractants, which can promote microglial accumulation to the site of tumor (145). For example, monocyte chemoattractant protein-3 (MCP-3) produced by glioma contributes to the microglia/macrophage(MG/MP) recruitment to gliomas and spreading rapidly in glioma by binding with its specific receptor CCR2 expressed on the MG/MP (146). In addition, the transmembrane chemokine CX3CL1 and its receptor CX3CR1 are also involved in the trafficking. It was demonstrated that CX3CR1 is highly expressed in solid human astrocytomas, glioblastomas and microglia, and the binding of CX3CL1 and CX3CR1 significantly promotes the migration of cultured human glioma-infiltrating microglia/macrophages in vitro(147). Besides, other factors such as hepatocyte growth factor (HGF) and its receptor Met, stem cell factor (SCF) and its receptor c-kit also demonstrate the interaction between microglia and tumor. Furthermore, several studies showed that the activated and migrated microglia caused by glioma can secret a plethora of factors, which in turn modulate the behaviors of tumor again. For instance, HGF produced by glioma could attract the microglia to the tumor through their Met receptor, meanwhile, the HGF secreted by microglia promotes the angiogenesis, cell motility, chemoattraction and invasion of tumor (148).

TNF-α, as an potent proinflammatory cytokine, its influence in the brain tumor is also discussed extensively. It was showed that microglia are the major source of TNF-α in glioma(149). Several in vitro studies shows that TNF-α can increase the expression of growth factor receptor including VEGFR, EGFR and HGFR in glioma cells. And generous studies have demonstrated that activated microglia can produce a great deal of growth factors such as EGF, VEGF and HGF, and the latters were demonstrated to promote the angiogenesis, glioma survival, cell proliferation and invasiveness(150;151). In addition, TNF-α has been showed that it can significantly increase the expression of MMP-9 in gliomas, while MMP-9 was proved to play a critical role in the brain tumor invasion (152).

Interleukin 10 (IL-10) is a cytokine with a broad spectrum of immunosuppressive activity, but its effect on the oncogenesis of gliomas is still unknown. Huettner once reported that the expression levels of IL-10 produced by microglia significantly increased with malignancy of the gliomas in vivo(153). In vitro study also showed that IL-10 increased glioma cell proliferation and motility significantly, and administration of IL-10 specific antibody blocked the effects (154) indicating that IL-10 participates in the progression of glioma, which is consistent with the results of Behnam (155).

Prostaglandins E(PGE), another immunosuppressant released from microglia in gliomas, was also reported to be involved in the oncogenesis of gliomas. Mandapathil reported that PGE can suppress the host immune response, weaken the immune surveillance against tumor cells and thereby promote the progress of tumor (156). The results of Badie showed that glioma-infiltrating microglia are a major source of PGE2 production through the COX-2 pathway and inhibition of cyclooxygenase-2(COX-2) decreases the blood-tumor barrier permeability, (135) suggesting that PGE may suppresses the leukocyte infiltration into tumors(6). In vitro study also demonstrated that the cytolytic activity of circulating peripheral blood leukocytes and tumor that had been activated with IL-2 was greatly decreased in the presence of PGE. Nowadays, the selective inhibition of COX-2 become the research focus and present a therapeutic potential for gliomas in clinic.

3.3.3. Therapeutic potential of microglia activation in brain tumor

Microglia are potent immune effector cells and mediate both innate and adaptive responses when they were activated in CNS injury and disease. Although in brain tumor, a high number of microglia is recruited. the microglia associated with glioma do not inducing an effective anti-tumor T cell response as they do in CNS inflammation. It was reported that factors secreted by microglia such as IL-10, TNF-α can suppress the immune response in glioma. So, Glioma-induced immunosuppression of microglia function becomes a great obstacle of anti-tumor therapy. Animal experiments showed that a single intratumoral injection of CpG oligodeoxynucleotide can keep a long term survival in animals with glioma, while animals depleted of macrophage/microglia were unable to reject the tumor after CpG treatment, indicating that microglia/macrophages are critical players in reducing the angiogenesis and tumor progression(157). It is suggested that targeting macrophages presents a potential strategy to control the tumor growth. In recent years, some studies focus on the macrophage polarization in tumor progression, which selectively tune their functions within a functional spectrum encompassing the M1 and M2 extremes. Macrophages can be phenotypically polarized by the microenvironment to mount specific M1 or M2 functional programs (158;159). M1 macrophages are generally considered potent effector cells which can produce copious amounts of pro-inflammatory cytokines and kill microorganisms and tumor cells. In contrast, M2 macrophages induced by various signaling molecules (e.g. IL-4, IL-13, glucocorticoids, IL-10, immunoglobulin complexes/TLR ligands) can tune inflammatory responses and adaptive Th2 immunity and promote the angiogenesis. This was consistent with that pharmacological skewing of tumor-associated macrophages polarization, from M2 to a full M1 phenotype, may sustain an anti-tumor activity (160). CNS microglia derived from monocyte precursor cells during embryogenesis(161) may also have similar properties to monocytes. Thus, polarized inflammation in brain tumor would be an interesting area of research. As the understanding of glioma progression, polarized inflammation induced by microglia may be a potential target of anticancer strategies.

4. CONCLUSION

Microglia are highly plastic cells and their activation states are regulated by the signals of the microenvironment. Now a bulk of experimental evidences indicate that microglia, depending on their states of activation and functional phenotype, can be either detrimental or supportive both in the intact and injured brain. Moreover, microglia are now recognized as the principal and necessary cells engaged in "CNS defense". The disease environment is a source of stimuli of microglia activation. So monitoring of microglia activation throughout the disease would give an indication of disease progression and more special markers need to be notarized (162). In addition, modulation of microglial activation will be a therapeutic target in future.

5. ACKNOWLEDGMENTS

Hui Zhang and Fu-Wu Wang equally contributed to this work. This research was supported by National Natural Science Foundation of China, Grant Number: No. 30771142; Natural Science Foundation of Shandong Province, Grant Number: No. Z2007C11, J200823; National Basic Research Program of China (973 Program, Grant Number: 2007CB512001, 2009CB941403; Key Research Program of Ministry of Education; Grant Number: No. 107069.

6. REFERENCE

1. MA Lynch: The multifaceted profile of activated microglia. Mol Neurobiol 40, 139-156 (2009).
doi:10.1007/s12035-009-8077-9

2. MB Graeber, WJ Streit: Microglia: biology and pathology. Acta Neuropathol. 119, 89-105 (2010).
doi:10.1007/s00401-009-0622-0

3. RB Panek, H Moses, JP Ting, EN Benveniste: Tumor necrosis factor alpha response elements in the HLA-DRA promoter: identification of a tumor necrosis factor alpha-induced DNA-protein complex in astrocytes. Proc Natl Acad Sci USA 59, 11518-11522 (1992).
doi:10.1073/pnas.89.23.11518

4. SC Morgan, DL Taylor, JM Pocock: Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades. J Neurochem 90, 89-101 (2004).
doi:10.1111/j.1471-4159.2004.02461.x

5. SM Park, JS Jung, MS Jang, KS Kang, SK Kang: Transforming growth factor-beta1 regulates the fate of cultured spinal cord-derived neural progenitor cells. Cell Prolif. 41, 248-264 (2008).
doi:10.1111/j.1365-2184.2008.00514.x

6. JJ Watters, JM Schartner, B Badie: Microglia function in brain tumors. J Neurosci Res. 81, 447-455 (2005).
doi:10.1002/jnr.20485

7. GJ Harry, CA McPherson, RN Wine, K Atkinson, C Lefebvred'Hellencourt: Trimethyltin-induced neurogenesis in the murine hippocampus. Neurotox Res 5, 623-627 (2004).
doi:10.1007/BF03033182

8. WJ Streit: Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40, 133-139 (2002).


9. SC Lee, W Liu, DW Dickson, CF Brosnan, JW Berman: Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol 150, 2659-2667 (1993).



10. CA Colton, DL Gilbert: Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 223, 284-288 (1987).
doi:10.1016/0014-5793(87)80305-8

11. J Liang, H Takeuchi, S Jin, M Noda, H Li, Y Doi, J Kawanokuchi, Y Sonobe, T Mizuno, A Suzumura: Glutamate induces neurotrophic factor production from microglia via protein kinase C pathway. Brain Res 1322, 8-23 (2010).
doi:10.1016/j.brainres.2010.01.083

12. C Kaur, V Sivakumar, ST Dheen, EA Ling: Insulin-like growth factor I and II expression and modulation in amoeboid microglial cells by lipopolysaccharide and retinoic acid. Neuroscience 138, 1233-1244 (2006).
doi:10.1016/j.neuroscience.2005.12.025

13. P Calissano, C Matrone, G Amadoro: Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease. Dev Neurobiol 70, 372-383 (2010).



14. B Connor, M Dragunow: The role of neuronal growth factors in neurodegenerative disorders of the human brain. Brain Res Brain Res Rev 27, 1-39 (1998).
doi:10.1016/S0165-0173(98)00004-6

15. A Flügel, K Matsumuro, H Neumann: Anti-inflammation activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur. J. Immunol. 31, 11-22 (2001).
doi:10.1002/1521-4141(200101)31:1<11::AID-IMMU11>3.0.CO;2-G

16. R Gong: Multi-target anti-inflammatory action of hepatocyte growth factor. Curr. Opin. Investig. Drugs 9, 1163-1170 (2008).

17. IG Onyango, JY Ahn, JB Tuttle, Jr JP Bennett, RH Swerdlow: Nerve growth factor attenuates oxidant-induced beta-amyloid neurotoxicity in sporadic Alzheimer's disease cybrids. J Neurochem 114, 1605-1618 (2010).
doi:10.1111/j.1471-4159.2010.06871.x

18. P Calissano, G Amadoro, C Matrone, S Ciafrè, R Marolda, V Corsetti, MT Ciotti, D Mercanti, A Di Luzio, C Severini, C Provenzano, N Canu: Does the term 'trophic' actually mean anti-amyloidogenic? The case of NGF. Cell Death Differ 17, 1126-1133 (2010).
doi:10.1038/cdd.2010.38

19. J Gunstad, A Benitez, J Smith, E Glickman, MB Spitznagel, T Alexander, J Juvancic-Heltzel, L Murray: Serum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults. J Geriatr Psychiatry Neurol 21, 166-170 (2008).
doi:10.1177/0891988708316860

20. WR Scha´┐Żbitz, C Berger, R Kollmar, M Seitz, E Tanay, M Kiessling, S Schwab, C Sommer: Effect of BDNF treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke 35, 992-997 (2004).
doi:10.1161/01.STR.0000119754.85848.0D

21. LF Lin, DH Doherty, JD Lile, S Bektesh, F Collins: GDNF: a glial cell linederived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130-1132 (1993).
doi:10.1126/science.8493557

22. L Croci, V Barili, D Chia, L Massimino, R van Vugt, G Masserdotti, R Longhi, P Rotwein, GG Consalez: Local insulin-like growth factor I expression is essential for Purkinje neuron survival at birth. Cell Death Differ (2010)(Epub ahead of print)



23. JK Ness, RC Jr Scaduto, TL Wood: IGF-I prevents glutamate-mediated bax translocation and cytochrome C release in O4+ oligodendrocyte progenitors. Glia 46, 183-194 (2004).



24. S Viswanathan, EA Ling, J LU, K Charanjit: Role of Glutamate and Its Receptors and Insulin-like Growth Factors in Hypoxia Induced Periventricular White Matter Injury. Glia 58, 507-523 (2010).


25. T Mizuno, M Sawada, T Marunouchi, A Suzumura: Production of interleukin-10 by mouse glial cells in culture. Biochem Biophys Res Commun 205, 1907-1915 (1994).
doi:10.1006/bbrc.1994.2893

26. H Ooboshi, S Ibayashi, T Shichita, Y Kumai, J Takada, T Ago, S Arakawa, H Sugimori, M Kamouchi, T Kitazono, M Iida: Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation 111(7), 913-919 (2005).
doi:10.1161/01.CIR.0000155622.68580.DC

27. Y Pang, S Rodts-Palenik, Z Cai, WA Bennett, PG Rhodes: Suppression of glial activation is involved in the protection of IL-10 on maternal E. coli induced neonatal white matter injury. Brain Res Dev Brain Res 157, 141-149 (2005).
doi:10.1016/j.devbrainres.2005.03.015

28. E Molina-Holgado, JM Vela, A Arévalo-Martín, C Guaza: LPS/IFN-gamma cytotoxicity in oligodendroglial cells: Role of nitric oxide and protection by the anti-inflammatory cytokine IL-10. Eur J Neurosci 13, 493-502 (2001).
doi:10.1046/j.0953-816x.2000.01412.x

29. E Molina-Holgado, A Arévalo-Martín, S Ortiz, JM Vela, C Guaza: Theiler's virus infection induces the expression of cyclooxygenase-2 in murine astrocytes: Inhibition by the anti-inflammatory cytokines interleukin-4 and interleukin-10. Neurosci Lett 324, 237-241 (2002).
doi:10.1016/S0304-3940(02)00209-4

30. SM Knoblach, AI Faden: Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol 153, 143-151 (1998).
doi:10.1006/exnr.1998.6877

31. H Guo, YX Jin, M Ishikawa, YM Huang, PH van der Meide, H Link, BG Xiao: Regulation of beta-chemokine mRNA expression in adult rat astrocytes by lipopolysaccharide, proinflammatory and immunoregulatory cytokines. Scand J Immunol 48, 502-508 (1998)
doi:10.1046/j.1365-3083.1998.00422.x

32. A Bachis, AM Colangelo, S Vicini, PP Doe, MA De Bernardi, G Brooker, I Mocchetti:

Interleukin-10 prevents glutamatemediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci 21, 3104-3112 (2001).



33. M Grilli, I Barbieri, H Basudev, R Brusa, C Casati, G Lozza, E Ongini: Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci 12, 2265- 2272 (2000).
doi:10.1046/j.1460-9568.2000.00090.x

34. K Pahan, M Khan, I Singh: Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase. J Neurochem 75, 576-582 (2000).
doi:10.1046/j.1471-4159.2000.0750576.x

35. S Klemen, JH Zhou, RB Suzanne, D.V Homer, WJ Rodney, GF Gregory, D Robert, WK Keith: IL-10 promotes survival of microglia without activating Akt. J Neuroimmunol 122, 9-19 (2002)
doi:10.1016/S0165-5728(01)00444-1

36. I Tesseur, K Zou, L Esposito, F Bard, E Berber, JV Can, AH Lin, L Crews, P Tremblay, P Mathews, L Mucke, E Masliah, T Wyss-Coray: Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J Clin Invest 116, 3060-3069 (2006).
doi:10.1172/JCI27341

37. B Schmierer, CS Hill: TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8,970-982 (2007).
doi:10.1038/nrm2297

38. TC Brionne, I Tesseur, E Masliah, T Wyss-Coray: Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 40, 1133-1145 (2003).
doi:10.1016/S0896-6273(03)00766-9

39. J Chin, A Angers, LJ Cleary, A Eskin, JH Byrne: Transforming growth factor beta1 alters synapsin distribution and modulates synaptic depression in Aplysia. J Neurosci 22, RC220 (2002).


40. VA Fadok, DL Bratton, A Konowal, PW Freed, JY Westcott, PM Henson: Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/ paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101, 890-898 (1998).
doi:10.1172/JCI1112

41. MA Perrella, C Patterson, L Tan, SF Yet, CM Hsieh, M Yoshizumi, ME Lee: Suppression of interleukin-1beta-induced nitricoxide synthase promoter/enhancer activity by transforming growth factor-beta1 in vascular smooth muscle cells. Evidence for mechanisms other than NF-kappaB. J Biol Chem 271, 13776-13780 (1996).
doi:10.1074/jbc.271.23.13776

42. JJ Li, J Lu, C Kaur, V Sivakumar, CY Wu, EA Ling: Effects of hypoxia on expression of transforming growth factor-beta1 and its receptors I and II in the amoeboid microglial cells and murine BV-2 cells. Neuroscience 156, 662-672 (2008).
doi:10.1016/j.neuroscience.2008.07.061

43. WC Huang, FC Yen , FS Shie , CM Pan , YJ Shiao , CN Yang , FL Huang , YJ Sung , HJ Tsay: TGF-beta1 blockade of microglial chemotaxis toward Abeta aggregates involves SMAD signaling and down-regulation of CCL5. J Neuroinflammation 7, 28 (2010).
doi:10.1186/1742-2094-7-28

44. R Schlapbach, KS Spanaus, U Malipiero, S Lens, A Tasinato, J Tschopp, A Fontana: TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. Eur J Immunol 30, 3680-3688 (2000).
doi:10.1002/1521-4141(200012)30:12<3680::AID-IMMU3680>3.0.CO;2-L

45. RM,Ransohoff VH Perry: Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27, 119-145 (2009).
doi:10.1146/annurev.immunol.021908.132528

46. A Rappert, I Bechmann, T Pivneva, J Mahlo, K Biber, No C lte, AD Kovac, C Gerard, HW Boddeke, R Nitsch, H Kettenmann: CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci 24, 8500-8509 (2004).
doi:10.1523/JNEUROSCI.2451-04.2004

47. AE Cardona, EP Pioro, ME Sasse, V Kostenko, SM Cardona, IM Dijkstra, D Huang, G Kidd, S Dombrowski, D R utta, JC Lee, DN Cook, S Jung, SA Lira, DR Littman, RM Ransohoff: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9, 917-924 (2006).
doi:10.1038/nn1715

48. DE Martin, FJ Chiu, I Gigli, HJ Muller-Eberhard: Killing of human melanoma cells by the membrane attack complex of human complement as a function of its molecular composition. J Clin Invest 80, 226-233 (1987).
doi:10.1172/JCI113052

49. W Lisa, N Harald: Role of microglia in neuronal degeneration and regeneration. Semin Immunopathol 31, 513-525 (2009).
doi:10.1007/s00281-009-0180-5

50. J Husemann, JD Loike, R Anankov, M Febbraio, SC Silverstein: Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40, 195-205 (2002).


51. CY Lee, GE Landreth: The role of microglia in amyloid clearance from the AD brain. J Neural Transm 117, 949-960 (2010).
doi:10.1007/s00702-010-0433-4

52. CH Lee, SM Moon, KY Yoo, JH Choi, OK Park, IK Hwang, Y Sohn, JB Moon, JH Cho, MH Won: Long-term changes in neuronal degeneration and microglial activation in the hippocampal CA1 region after experimental transient cerebral ischemic damage. Brain Res 1342, 138-149 (2010).
doi:10.1016/j.brainres.2010.04.046

53. X Wang, Y Suzuki: Microglia produce IFN-gamma independently from T cells during acute toxoplasmosis in the brain. J Interferon Cytokine Res 27, 599-605 (2007).
doi:10.1089/jir.2006.0157

54. T Mizuno, T Kurotani, Y Komatsu, J Kawanokuchi, H Kato, N Mitsuma, A Suzumura: Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology 46, 404-411 (2004).
doi:10.1016/j.neuropharm.2003.09.009

55. H Kadhim, M Khalifa, P Deltenre, G Casimir, G Se′ bire: Molecular mechanisms of cell death in periventricular leukomalacia. Neurology 67, 293-299 (2006).
doi:10.1212/01.wnl.0000224754.63593.c4

56. T Nakazawa, C Nakazawa, A Matsubara, K Noda, T Hisatomi, H She, N Michaud, A Hafezi-Moghadam, J W Miller, LI Benowitz: Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci 26, 12633-12641 (2006).
doi:10.1523/JNEUROSCI.2801-06.2006

57. V Fontaine, S Mohand-Said, N Hanoteau, C Fuchs, K Pfizenmaier, U Eisel: Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci 22, RC216 (2002).


58. C Kaur, EA Ling: Periventricular white matter damage in the hypoxic neonatal brain: Role of microglial cells. Prog Neurobiol 87, 264-280 (2009).
doi:10.1016/j.pneurobio.2009.01.003

59. NJ Rothwell, GN Luheshi: Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 2, 618-625 (2000).
doi:10.1016/S0166-2236(00)01661-1

60. LC Parker, GN Luheshi, NJ Rothwell, E Pinteaux: IL-1 beta signalling in glial cells in wildtype and IL-1RI deficient mice. Br J Pharmacol 136, 312-320 (2002).
doi:10.1038/sj.bjp.0704715

61. Y Deng, J Lu, V Sivakumar, EA Ling, C Kaur: Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol 18, 387-400 (2008).
doi:10.1111/j.1750-3639.2008.00138.x

62. JM Vela, E Molina-Holgado, A Are′ valo-Martin, G Almaza′ n, C Guaza: Interleukin-1 regulates proliferation and differentiation of oligodendrocyte progenitor cells. Mol Cell Neurosci 20, 489-502 (2002).
doi:10.1006/mcne.2002.1127

63. RB Rock, G Gekker, S Hu, WS Sheng, M Cheeran, JR Lokensgard, PK Peterson: Role of microglia in central nervous system infections. Clin Microbiol Rev 17, 942-964 (2004).
doi:10.1128/CMR.17.4.942-964.2004

64. RL Haynes, O Baud, J Li, HC Kinney, JJ Volpe, DR Folkerth: Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol 15, 225-233 (2005).
doi:10.1111/j.1750-3639.2005.tb00525.x

65. RN Saha, K Pahan: Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid Redox Signal 8, 929-947 (2006).
doi:10.1089/ars.2006.8.929

66. R Pannu, I Singh: Pharmacological strategies for the regulation of inducible nitric oxide synthase: neurodegenerative versus neuroprotective mechanisms. Neurochem Int 49, 170-182 (2006).
doi:10.1016/j.neuint.2006.04.010

67. C Kaur, V Sivakumar, LS Ang, A Sundaresan: Hypoxic damage to the periventricular white matter in neonatal brain: role of vascular endothelial growth factor, nitric oxide and excitotoxicity. J Neurochem 98, 1200-1216 (2006).
doi:10.1111/j.1471-4159.2006.03964.x

68. LI Bruijn, TM Miller, DW Cleveland: Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 27, 723-749 (2004).
doi:10.1146/annurev.neuro.27.070203.144244

69. M Schwartz, I Shaked, J Fishe, T Mizrahi, H Schori: Protective autoimmunity against the enemy within: fighting glutamate toxicity. Trends Neurosci 26, 297-302 (2003).
doi:10.1016/S0166-2236(03)00126-7

70. H Takeuchi, Mizuno, G Zhang, J Wang, J Kawanokuchi, R Kuno, A Suzumura: Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem 280, 10444-10454 (2005).
doi:10.1074/jbc.M413863200

71. H Takeuchi, S Jin, J Wang, G Zhang, J Kawanokuchi, R Kuno, Y Sonobe, T Mizuno, A Suzumura: Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281, 21362-21368 (2006).
doi:10.1074/jbc.M600504200

72. J Liang, H Takeuchi, Y Doi, J Kawanokuchi, Y Sonobe, S Jin, I Yawata, H Li, S Yasuoka, T Mizuno, A Suzumura: Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res 1210, 11-19 (2008).
doi:10.1016/j.brainres.2008.03.012

73. NC Danbolt: Glutamate uptake. Prog Neurobiol 65, 1-105 (2001).
doi:10.1016/S0301-0082(00)00067-8

74. AM Arranz, A Hussein, JJ Alix, F Pérez-Cerdá, N Allcock, C Matute, R Fern: Functional glutamate transport in rodent optic nerve axons and glia. Glia 56, 1353-1367 (2008).

75. AM Arranz, M Gottlieb, F Pérez-Cerdá, C Matute: Increased expression of glutamate transporters in subcortical white matter after transient focal cerebral ischemia. Neurobiology of Disease 37, 156-165 (2010).
doi:10.1016/j.nbd.2009.09.019


76. M Domercq, MV Sánchez-Gómez, C Sherwin, E Etxebarria, R Fern, C Matute: System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes.J Immunol 178(10), 6549-6556 (2007).


77. F Doetsch, I Caille, DA Lim, JM Garcia-Verdugo, A Alvarez-Buylla: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703-716 (1999).


78. G Kempermann, L Wiskott, FH Gage: Functional significance of adult neurogenesis. Curr Opin Neurobiol 14, 186-191 (2004).
doi:10.1016/j.conb.2004.03.001


79. FH Gage: Mammalian neural stem cells. Science 287, 1433-1438 (2000).
doi:10.1126/science.287.5457.1433

80. A Alvarez-Buylla, DA Lim: For the long run: Maintaining germinal niches in the adult brain. Neuron 41, 83-86 (2004).
doi:10.1016/S0896-6273(04)00111-4


81. H Song, C Stevens, FH Gage: Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39-44 (2002).
doi:10.1038/417039a

82. NM Walton, BM Sutter, ED Laywell, LH Levkoff, SM Kearns, GP II Marshall, B Scheffler, DA Steindler: Microglia instruct subventricular zone neurogenesis. Glia 54, 815-825 (2006).


83. P Zhu, R Hata, F Cao, F Gu, Y Hanakawa, K Hashimoto, M Sakanaka: Ramified microglial cells promote astrogliogenesis and maintenance of neural stem cells through activation of Stat3 function. FASEB J 22, 3866-3877 (2008).
doi:10.1096/fj.08-105908

84. VH Perry, TA Newman, C Cunningham: The impact of systemic infection on the progression of neurodegenerative disease. Nature Rev Neurosci 4, 103-112 (2003).
doi:10.1038/nrn1032

85. I Napoli, K Kierdorf, H Neumann: Microglial precursors derived from mouse embryonic stem cells. Glia 57, 1660-1671 (2009).


86. ML Monje, H Toda, TD Palmer: Inflammatory blockade restores adult hippocampal neurogenesis. Science 302,1760-1765 (2003).
doi:10.1126/science.1088417

87. E Cacci, MA Ajmone-Cat Anelli, S Biagioni, L Minghetti: In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia. Glia 56, 412-425 (2008).



88. L Vallieres, IL Campbell, FH Gage, PE Sawchenko: Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22, 486-492 (2002).


89. M Nakanishi, T Niidome, S Matsuda, A Akaike, T Kihara, H Sugimoto: Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci, 25, 649-658 (2007).
doi:10.1111/j.1460-9568.2007.05309.x

90. O Islam, X Gong, S Rose-John, K Heese: Interleukin-6 and neural stem cells: more than gliogenesis. Mol Biol Cell 20, 88-99 (2009).
doi:10.1091/mbc.E08-05-0463

91. MK Kang, SK Kang: Interleukin-6 induces proliferation in adult spinal cord-derived neural progenitors via the JAK2/STAT3 pathway with EGF-induced MAPK phosphorylation. Cell Prolif 41, 377-392 (2007).
doi:10.1111/j.1365-2184.2008.00537.x

92. E Cacci, JH Claasen, Z Kokaia: Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J Neurosci Res 80, 789-797 (2005).
doi:10.1002/jnr.20531

93. YP Liu, HI Lin, SF Tzeng: Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture. Brain Res 1054, 152-158 (2005).
doi:10.1016/j.brainres.2005.06.085


94. JP Wu, JS Kuo, YL Liu, SF Tzeng: Tumor necrosis factor-alpha modulates the proliferation of neural progenitors in the subventricular/ ventricular zone of adult rat brain. Neurosci Lett 292, 203-206 (2000).
doi:10.1016/S0304-3940(00)01472-5

95. D Widera, I Mikenberg, M Elvers, C Kaltschmidt, B Kaltschmidt: Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling. BMC Neurosci 7, 64 (2006).
doi:10.1186/1471-2202-7-64

96. U Heldmann, P Thored, JH Claasen, A Arvidsson, Z Kokaia, O Lindvall: TNF-alpha antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain. Exp Neurol 19, 204-208 (2005).
doi:10.1016/j.expneurol.2005.07.024


97. RE Iosif, CT Ekdahl, H Ahlenius, CJ Pronk, S Bonde, Z Kokaia, SE Jacobsen, O Lindvall: Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci 26, 9703-9712 (2006).
doi:10.1523/JNEUROSCI.2723-06.2006

98. JW Koo, RS Duman: IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci 105, 51-56 (2008).
doi:10.1073/pnas.0708092105

99. O Ben Menachem-Zidon, I Goshen, T Kreisel, Y Ben Menahem, E Reinhartz, T Ben Hur, R Yirmiya: Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis. Neuropsychopharmacology. 33, 2251-2262 (2008).
doi:10.1038/sj.npp.1301606

100. X Wang, S Fu, Y Wang, P Yu, J Hu, W Gu, XM Xu, P Lu: Interleukin-1beta mediates proliferation and differentiation of multipotent neural precursor cells through the activation of SAPK/JNK pathway. Mol Cell Neurosci 36, 343-354 (2007).
doi:10.1016/j.mcn.2007.07.005

101. T Ben-Hur, O Ben-Menachem, V Furer, O Einstein, R Mizrachi-Kol, N Grigoriadis: Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells. Mol Cell Neurosci. 24, 623-631 (2003).
doi:10.1016/S1044-7431(03)00218-5

102. MC Cheeran, Z Jiang, S Hu, HT Ni, JM Palmquist, JR Lokensgard: Cytomegalovirus infection and interferon-gamma modulate major histocompatibility complex class I expression on neural stem cells. J Neurovirol 14, 437-447 (2008).
doi:10.1080/13550280802356845

103. O Butovsky, Y Ziv, A Schwartz, G Landa, AE Talpalar, S Pluchino, G Martino, M Schwartz: Microglia activated by IL-4 or IFNgamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31, 149-160 (2006).
doi:10.1016/j.mcn.2005.10.006

104. G Wong, Y Goldshmit, AM Turnley: Interferon-gamma but not TNF alpha promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Exp Neurol 187, 171-177 (2004).
doi:10.1016/j.expneurol.2004.01.009


105. JH Song, CX Wang, DK Song, P Wang, A Shuaib, C Hao: Interferon gamma induces neurite outgrowth by up-regulation of p35 neuron-specific cyclin-dependent kinase 5 activator via activation of ERK1/2 pathway. J Biol Chem 280, 12896-12901 (2005).
doi:10.1074/jbc.M412139200

106. S Johansson, J Price, M Modo: Effect of inflammatory cytokines on major histocompatibility complex expression and differentiation of human neural stem/progenitor cells. Stem Cells 26, 2444-2454 (2008).
doi:10.1634/stemcells.2008-0116

107. SJ Kim, TG Son, K Kim, HR Park, MP Mattson, J Lee: Interferon-gamma promotes differentiation of neural progenitor cells via the JNK pathway. Neurochem Res 32, 1399-1406 (2007).
doi:10.1007/s11064-007-9323-z

108. R Baron, A Nemirovsky, I Harpaz, H Cohen, T Owens, A Monsonego: IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease. FASEB J 22, 2843-2852 (2008).
doi:10.1096/fj.08-105866

109. CT Ekdahl, Z Kokaia, O Lindvall: Brain inflammation and adult neurogenesis: the dual role of microglia. Neurosci 158, 1021-1029 (2009).
doi:10.1016/j.neuroscience.2008.06.052


110. MA Packer, Y Stasiv, A Benraiss, E Chmielnick i, A Grinberg, H Westphal, SA Goldman, G Enikolopov: Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci 100, 9566-9571 (2003).
doi:10.1073/pnas.1633579100

111. B Moreno-Lopez, C Romero-Grimaldi, JA Noval, M Murillo-Carretero, ER Matarredona, C Estrada: Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. J Neurosci 24, 85-95 (2004).
doi:10.1523/JNEUROSCI.1574-03.2004

112. A Torroglosa, M Murillo-Carretero, C Romero-Grimaldi, ER Matarredona, A Campos-Caro, C Estrada: Nitric oxide decreases subventricular zone stem cell proliferation by inhibition of epidermal growth factor receptor and phosphoinositide-3-kinase/Akt pathway. Stem Cells 25, 88-97 (2007).
doi:10.1634/stemcells.2006-0131

113. A Reif, A Schmitt, S Fritzen, S Chourbaji, C Bartsch, A Urani, M Wycislo, R Mossner, C Sommer, P Gass, KP Lesch: Differential effect of endothelial nitric oxide synthase (NOS-III) on the regulation of adult neurogenesis and behaviour. Eur J Neurosci 20, 885-895 (2004).
doi:10.1111/j.1460-9568.2004.03559.x

114. A Cardenas, MA Moro, O Hurtado, JC Leza, I Lizasoain: Dual role of nitric oxide in adult neurogenesis. Brain Res Brain Res Rev 50, 1-6 (2005).
doi:10.1016/j.brainresrev.2005.03.006

115. L Corsani, E Bizzoco, F Pedata, M Gianfriddo, MS Faussone-Pellegrini, MG Vannucchi: Inducible nitric oxide synthase appears and is co-expressed with the neuronal isoform in interneurons of the rat hippocampus after transient ischemia induced by middle cerebral artery occlusion. Exp Neurol 211, 433-440 (2008).
doi:10.1016/j.expneurol.2008.02.008

116. DK Arora, AS Cosgrave, MR Howard, V Bubb, JP Quinn, T Thippeswamy: Evidence of postnatal neurogenesis in dorsal root ganglion: role of nitric oxide and neuronal restrictive silencer transcription factor. J Mol Neurosci. 32, 97-107 (2007).
doi:10.1007/s12031-007-0014-7

117. Y Koriyama, R Yasuda, K Homma, K Mawatari, M Nagashima, K Sugitani, T Matsukawa, S Kato: Nitric oxide-cGMP signaling regulates axonal elongation during optic nerve regeneration in the goldfish in vitro and in vivo. J Neurochem 110, 890-901 (2009).
doi:10.1111/j.1471-4159.2009.06182.x

118. C Holscher: Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci 20, 298-303 (1997).
doi:10.1016/S0166-2236(97)01065-5


119. L Sülz, G Astorga, B Bellette, R Iturriaga, A Mackay-Sim, J Bacigalupo: Nitric oxide regulates neurogenesis in adult olfactory epithelium in vitro. Nitric Oxide 20, 238-252 (2009).
doi:10.1016/j.niox.2009.01.004

120. S Das, A Basu: Inflammation: a new candidate in modulating adult neurogenesis. J Neurosci Res 86, 1199-1208 (2008).
doi:10.1002/jnr.21585

121. A Belmadani, PB Tran, D Ren, S Assimacopoulos, EA Grove, RJ Miller: The chemokine stromal cell-derived factor-1 regulates the migration of sensory neuron progenitors. J Neurosci 25, 3995-4003 (2005).
doi:10.1523/JNEUROSCI.4631-04.2005

122. MD Krathwohl, JL Kaiser: Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 22, 109-118 (2004).
doi:10.1634/stemcells.22-1-109

123. HT Ni, S Hu, WS Sheng, JM Olson, MC Cheeran, AS Chan, JR Lokensgard, PK Peterson: High-level expression of functional chemokine receptor CXCR4 on human neural precursor cells. Brain Res Dev Brain Res 152, 159-169 (2004).
doi:10.1016/j.devbrainres.2004.06.015

124. P Thored, A Arvidsson, E Cacci, H Ahlenius, T Kallur, V Darsalia, CT Ekdahl, Z Kokaia, O Lindvall: Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 24, 739-747 (2006).
doi:10.1634/stemcells.2005-0281

125. J Imitola, K Raddassi, KI Park, FJ Mueller, M Nieto, YD Teng, D Frenkel, J Li, RL Sidman, CA Walsh, EY Snyder, SJ Khour: Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci 101, 18117-18122 (2004).
doi:10.1073/pnas.0408258102


126. M Dziembowska, TN Tham, P Lau, S Vitry, F Lazarini, M Dubois-Dalcq: A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia 50, 258-269 (2005).


127. PB Tran, RJ Miller: HIV-1, chemokines and neurogenesis. Neurotox Res 8, 149-158 (2005).
doi:10.1007/BF03033826

128. NP Whitney, TM Eidem, H Peng, Y Huang, JC Zheng: Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem. 108, 1343-1359 (2009).
doi:10.1111/j.1471-4159.2009.05886.x


129. P Taupin: A dual activity of ROS and oxidative stress on adult neurogenesis and Alzheimer's disease. Cent Nerv Syst Agents Med Chem 10, 16-21 (2010).


130. KG Bath, FS Lee: Neurotrophic factor control of adult SVZ neurogenesis. Dev Neurobiol 70, 339-349 (2010).


131. Y Kuwabara, A Yokoyama, L Yang, K Toku, K Mori, I Takeda, T Shigekawa, B Zhang, N Maeda, M Sakanaka, J Tanaka: Two populations of microglial cells isolated from rat primary mixed glial cultures. J Neurosci Res 73, 22-30 (2003).
doi:10.1002/jnr.10637

132. M Wirenfeldt, AA Babcock, R Ladeby, KL Lambertsen, F Dagnaes-Hansen, RG Leslie, T Owens, B Finsen: Reactive microgliosis engages distinct responses by microglial subpopulations after minor central nervous system injury. J Neurosci Res 82, 507-514 (2005).
doi:10.1002/jnr.20659

133. W Roggendorf, S Strupp, W Paulus: Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol 92, 288-293 (1996).
doi:10.1007/s004010050520

134. B Badie, JM Schartner, J Paul, BA Bartley, J Vorpahl, JK Preston: Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study. J Neurosurg 93, 634-639 (2000).
doi:10.3171/jns.2000.93.4.0634

135. B Badie, JM Schartner, AR Hagar, S Prabakaran, TR Peebles, B Bartley, S Lapsiwala, DK Resnick, J Vorpahl: Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation. Clin Cancer Res 9, 872-877 (2003).

136. JM Schartner, AR Hagar, M Van Handel: Impaired capacity for upregulation of MHC class II in tumor-associated microglia. Glia 51, 279-285 (2005).


137. I Bettinger, S Thanos, W Paulus: Microglia promote glioma migration. Acta Neuropathol 103, 351-355 (2002).
doi:10.1007/s00401-001-0472-x

138. I Yang, SJ Han, G Kaur, C Crane, AT Parsa: The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17, 6-10 (2010).
doi:10.1016/j.jocn.2009.05.006

139. CT Tran, P Wolz, R Egensperger, S Kosel, Y Imai, K Bise, S Kohsaka, P Mehraein, MB Graeber: Differential expression of MHC class II molecules by microglia and neoplastic astroglia: relevance for the escape of astrocytoma cells from immune surveillance. Neuropathol Appl Neurobiol 24, 293-301 (1998).
doi:10.1046/j.1365-2990.1998.00120.x

140. A Flugel, MS Labeur, EM Grasbon-Frodl, GW Kreutzberg, MB Graeber: Microglia only weakly present glioma antigen to cytotoxic T cells. Int J Dev Neurosci 17, 547-556 (1999).
doi:10.1016/S0736-5748(99)00020-9

141. A Ghosh, S Chaudhuri: Microglial action in glioma: A boon turns bane. Immunol Lett 131, 3-9 (2010).
doi:10.1016/j.imlet.2010.03.003

142. YJ Kim, S Hwang Y, ES Oh, S Oh, IO Han: IL-1β, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-κB pathways. J Neurosci Res 84, 1037-1046 (2006).
doi:10.1002/jnr.21011

143. YJ Kim, SY Hwang, JS Hwang, JW Lee, ES Oh, IO Han: C6 glioma cell insoluble matrix components enhance interferon-γ-stimulated inducible nitric-oxide synthase/nitric oxide production in BV2 microglial cells. J Biol Chem 283, 2526-2533 (2008).
doi:10.1074/jbc.M610219200

144. GG Gomez, CA Kruse: Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther Mol Biol 10, 133-146 (2006).


145. K Frei, D Piani, UV Malipiero, E Van Meir, N de Tribolet, A Fontana: Granulocyte-macrophage colony-stimulating factor (GM-CSF) production by glioblastoma cells. Despite the presence of inducing signals GM-CSF is not expressed in vivo. J Immunol 148, 3140-3146 (1992).

146. M Okada, M Saio, Y Kito, N Ohe, H Yano, S Yoshimura: Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int J Oncol 34, 1621-1627 (2009).


147. J Held-Feindt, K Hattermann, S S Müerköster, H Wedderkopp, F Knerlich-Lukoschus, H Ungefroren, H M Mehdorn, R Mentlein: CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). Experimental cell Res 316, 1553-1566 (2010).
doi:10.1016/j.yexcr.2010.02.018

148. P Kunkel, S Müller, P Schirmacher, D Stavrou, R Fillbrandt, M Westphal, K Lamszus: Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas. Neuro Oncol 3(2), 82-88 (2001).


149. C Hao, IF Parney, WH Roa, J Turner, KC Petruk, DA Ramsay: Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation. Acta Neuropathol 103, 171-178 (2002).
doi:10.1007/s004010100448

150. C Nolte, F Kirchhoff, H Kettenmann: Epidermal growth factor is a motility factor for microglial cells in vitro: evidence for EGF receptor expression. Eur J Neurosci 9, 1690-1698 (1997).
doi:10.1111/j.1460-9568.1997.tb01526.x

151. F Forstreuter, R Lucius, R Mentlein: Vascular endothelial growth factor induces chemotaxis and proliferation of microglial cells. J Neuro immunol 132, 93-98 (2002).
doi:10.1016/S0165-5728(02)00315-6

152. PO Esteve, E Chicoine, O Robledo, F Aoudjit, A Descoteaux, EF Potworowski, Y St-Pierre: Protein kinase C-zeta regulates transcription of the matrix metalloproteinase-9 gene induced by IL-1 and TNFalpha in glioma cells via NF-kappa B. J Biol Chem 277, 35150-35155 (2002).
doi:10.1074/jbc.M108600200

153. C Huettner, S Czub, S Kerkau, W Roggendorf, JC Tonn: Interleukin10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro. Anticancer Res 17, 3217-3224 (1997).

154. V Samaras, C Piperi, P Korkolopoulou, A Zisakis, G Levidou, MS Themistocleous, EI Boviatsis, DE Sakas, RW Lea, A Kalofoutis, E Patsouris: Application of the ELISPOT method for comparative analysis of interleukin(IL)-6 and IL-10 secretion in peripheral blood of patients with astroglia tumor. Mol Cell Biochem 304(1-2), 343-351 (2007).
doi:10.1007/s11010-007-9517-3

155. B Badie, J Schartner: Role of microglia in glioma biology. Microscopy Research and Technique 54, 106-113 (2001).
doi:10.1002/jemt.1125

156. M Mandapathil, MJ Szczepanski, M Szajnik, J Ren, EK Jackson, JT Johnson, E Gorelik, S Lang, TL Whiteside: Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem 285, 27571-27580 (2010).
doi:10.1074/jbc.M110.127100


157. G Auf, AF Carpentier, L Chen: Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen. Clin Cancer Res 7, 3540-3543 (2001).


158. A Mantovani, S Sozzani, M Locati, P Allavena, A Sica: Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23, 549-555 (2002).
doi:10.1016/S1471-4906(02)02302-5

159. F Geissmann, S Jung, DR Littman: Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 1, 71-82 (2003).
doi:10.1016/S1074-7613(03)00174-2

160. S Antonio, L Paola, M Alessandra, R Luca, P Chiara, G T Maria, R Monica, K B Subhra, A Paola, M Alberto: Macrophage polarization in tumour progression. Semin Cancer Biol 18, 349-355 (2008).
doi:10.1016/j.semcancer.2008.03.004

161. EA Ling, WC Wong: The origin and nature of ramified and amoeboid microglia: a historical review and current concepts. Glia 7, 9-18 (1993).


162. LB Michelle, Z Luigi, H Jau-Shyong: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Neuroscience 8, 57-69 (2007).

Key Words: Microglia; Inflammation; Neurogenesis; Brain Tumor, Review

Send correspondence to: Ai-jun Hao, Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, No.44, Wenhua Xi Road, Jinan, Shandong, 250012, PR China, Tel: 86 0531-88382050, Fax: 86 0531-88382502, E-mail:aijunhao@sdu.edu.cn