Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy

López-Redondo, Fernando; Nakajima, Kazuyuki; Honda, Shizuyo; Kohsaka, Shinichi

doi:10.1016/s0169-328x(00)00022-x

Cited by 108 publications

(82 citation statements)

References 37 publications

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“…We propose that a spatial segregation of T cell-astrocyte interaction may be important for this glutamate-based neuroprotective response. Microglia also express glutamate transporters (10,(52)(53)(54)(55), whose levels are further increased in activated microglia following nerve injury (56). Microglia have been suggested to potentially function as the "middlemen" in T cell-mediated neuroprotection (10, 57), due to their abundance at the epicenter of injury sites.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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A well-controlled T cell response to CNS injury may result in increased neuronal survival. However, the precise mechanism of T cell-induced neuroprotection is unknown. In this study, we report the unexpected finding that during culture of T cells, high levels of glutamate accumulate, which are efficiently cleared if T cells are cocultured with astrocytes. The T cell-derived glutamate elicits in turn, the release of neuroprotective thiols (cysteine, glutathione, and cysteinyl-glycine) and lactate from astrocytes. Media obtained from astrocytes conditioned in the presence of T cells reduce neuronal apoptosis induced by oxidative stress in primary neuronal cultures from 48 ± 14 to 9 ± 4% (p < 0.001). Inhibition of glutamate-dependent signaling during astrocyte-T cell cocultivation by a glutamate uptake inhibitor, l-aspartic acid β-hydroxamate, abolishes this neuroprotective effect. The ability of astrocytes to clear extracellular glutamate is impaired under conditions of oxidative stress. We demonstrate that T cells, via secreted cytokines, restore glutamate clearance capacity of astrocytes under oxidative conditions. Furthermore, under normoxic conditions, glutamate-buffering capacity of astrocytes is increased upon cocultivation with T cells. It is known that, following CNS injury, astrocytes can respond with beneficial or destructive effects on neurons. However, the context and signaling mechanisms for this dual astrocytic response are unknown. Our results implicate T cells as potential determinants of the context that elicits a protective role for astrocytes in the damaged CNS.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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“…Microglia also robustly express functional TRPM7 channels, 54 which can conduct large inward monovalent currents; e.g., when extracellular pH is reduced to levels that have been observed during tissue injury, ischemia, repetitive nerve activity or seizures. 55 In addition, activated microglia express high levels of Na + /glutamate co-transporters 56 which, in astrocytes, cause large glutamate-induced elevations in internal Na + . Extracellular glycine, which increases in ischemia, neurotrauma and epilepsy, elevates internal Na + in microglia through Na + -coupled neutral amino acid transporters.…”

Section: Discussionmentioning

confidence: 99%

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Newell

Stanley²,

Schlichter

2007

Channels

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KEy WordSmicroglia activation, brain macrophage, reversed sodium-calcium exchange, Slc8a, NCX1-3, superoxide production, quantitative real-time RT-PCR, phagocytosis, Ca 2+ paradox, perforated patch, SBFI imaging, Fura-2 imaging AbSTrACTPhagocytosis and the ensuing NADPH-mediated respiratory burst are important aspects of microglial activation that require calcium ion (Ca 2+ ) influx. However, the specific Ca 2+ entry pathway(s) that regulates this mechanism remains unclear, with the best candidates being surface membrane Ca 2+ -permeable ion channels or Na + /Ca 2+ exchangers. In order to address this issue, we used quantitative real-time RT-PCR to assess mRNA expression of the Na + /Ca 2+ exchangers, Slc8a1-3/NCX1-3, before and after phagocytosis by rat microglia. All three Na + /Ca 2+ exchangers were expressed, with mRNA levels of NCX1 > NCX3 > NCX2, and were unaltered during the one hour phagocytosis period. We then carried out a biophysical characterization of Na + /Ca 2+ exchanger activity in these cells. To investigate conditions under which Na + /Ca 2+ exchange was functional, we used a combination of perforated patch-clamp analysis, fluorescence imaging of a Ca 2+ indicator (Fura-2) and a Na + indicator (SBFI), and manipulations of membrane potential and intracellular and extracellular ions. Then, we used a pharmacological toolbox to compare the contribution of Na + /Ca 2+ exchange with candidate Ca 2+ -permeable channels, to the NADPH-mediated respiratory burst that was triggered by phagocytosis. We find that inhibiting the reversed mode of the Na + /Ca 2+ exchanger with KB-R7943, dose dependently reduced the phagocytosis-stimulated respiratory burst; whereas, blockers of store-operated Ca 2+ channels or L-type voltage-gated Ca 2+ channels had no effect. These results provide evidence that Na + /Ca 2+ exchangers are potential therapeutic targets for reducing the bystander damage that often results from microglia activation in the damaged CNS. AbbrEviATioNSCR3, complement receptor 3; DPI, diphenylene iodonium; FBS, fetal bovine serum; HPRT1, hypoxanthine guanine phosphoribosyl transferase; IFNg, interferon-gamma; IL1b, interleukin 1 beta; NADPH, nicotinamide adenine dinucleotide phosphate; NCX, Na + / Ca 2+ exchanger; NMDG + , n-methyl d-glucamine; qRT-PCR, quantitative real-time reverse transcriptase polymerase chain reaction; SERCA, smooth endoplasmic reticulum calcium ATPase; SOC, store-operated Ca 2+ channels; TNFa, tumor necrosis factor alpha

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“…Since 1995, several groups have demonstrated that primary microglia (Kondo et al, 1995;Lopez-Redondo et al, 2000;Nakajima et al, 1998;Noda et al, 1999;Rimaniol et al, 2000;Swanson et al, 1997), as well as resident spleen macrophages and monocyte-derived macrophages (MDM) (Rimaniol et al, 2000), express the two main glial high affinity glutamate transporters -excitatory amino acid transporter (EAAT)-1 and -2 -when activated (Fig. 2, B,C).…”

Section: Activated Macrophages and Microglia Express The Molecular Efmentioning

confidence: 99%

Macrophages and HIV-1: dangerous liaisons

Verani¹,

Gras

Pancino

2005

Molecular Immunology

102

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Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy

Cited by 108 publications

References 37 publications

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Macrophages and HIV-1: dangerous liaisons

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Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy

Cited by 108 publications

References 37 publications

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Reversed Na+/Ca2+Exchange Contributes to Ca2+Influx and Respiratory Burst in Microglia

Macrophages and HIV-1: dangerous liaisons

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Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia