Astrocyte-derived GDNF is a potent inhibitor of microglial activation

被引:145
作者
Rocha, Sandra Moreira [1 ]
Cristovao, Ana Clara [1 ]
Campos, Filipa Lopes [1 ]
Fonseca, Carla Pais [1 ]
Baltazar, Graca [1 ]
机构
[1] Univ Beira Interior, CICS UBI Hlth Sci Res Ctr, P-6200506 Covilha, Portugal
关键词
Neuroinflammation; Neurotrophic factors; Parkinson's disease; Microglia; Substantia nigra; GDNF; PROTECTS DOPAMINERGIC-NEURONS; EXCESSIVE BRAIN INFLAMMATION; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; INDUCED NEUROTOXICITY; SUBSTANTIA-NIGRA; GLIAL-CELLS; RAT-BRAIN; EXPRESSION; PHAGOCYTOSIS;
D O I
10.1016/j.nbd.2012.04.014
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Neuroinflammation is recognized as a major factor in Parkinson's disease (PD) pathogenesis and increasing evidence propose that microglia is the main source of inflammation contributing to the dopaminergic degeneration observed in PD. Several studies suggest that astrocytes could act as physiological regulators preventing excessive microglia responses. However, little is known regarding how astrocytes modulate microglial activation. In the present study, using Zymosan A-stimulated midbrain microglia cultures, we showed that astrocytes secrete factors capable of modulating microglial activation, namely its phagocytic activity and the production of reactive oxygen species since both parameters were highly diminished in cells incubated with astrocytes conditioned media (ACM). Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF) and brain-derived neurotrophic factor (BDNF), known to have a neuroprotective role in the nigrostriatal system, are among the candidates to be astrocyte-secreted molecules involved in the modulation of microglial activation. The effect of ACM on Zymosan A-induced microglial activation was abolished when the GDNF present in the ACM was abrogated using a specific antibody, but not when ACM was neutralized with anti-CDNF, anti-BDNF or with a heat-inactivated GDNF antibody. In addition, media conditioned by astrocytes silenced for GDNF were not able to prevent microglial activation, whereas supplementation of non-conditioned media with GDNF prevented the activation of microglia evoked by Zymosan A. Taken together, these results indicate that astrocyte-derived GDNF plays a major contribution to the control of midbrain microglial activation, suggesting that GDNF can protect from neurodegeneration through the inhibition of neuroinflammation. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:407 / 415
页数:9
相关论文
共 44 条
  • [1] DEMONSTRATION OF POLY-N-ACETYL LACTOSAMINE RESIDUES IN AMEBOID AND RAMIFIED MICROGLIAL CELLS IN RAT-BRAIN BY TOMATO LECTIN-BINDING
    ACARIN, L
    VELA, JM
    GONZALEZ, B
    CASTELLANO, B
    [J]. JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 1994, 42 (08) : 1033 - 1041
  • [2] A dual-hit animal model for age-related parkinsonism
    Boger, Heather A.
    Granholm, Ann-Charlotte
    McGinty, Jacqueline F.
    Middaugh, Lawrence D.
    [J]. PROGRESS IN NEUROBIOLOGY, 2010, 90 (02) : 217 - 229
  • [3] GDNF Selectively Induces Microglial Activation and Neuronal Survival in CA1/CA3 Hippocampal Regions Exposed to NMDA Insult through Ret/ERK Signalling
    Boscia, Francesca
    Esposito, Carla Lucia
    Di Crisci, Antonella
    de Franciscis, Vittorio
    Annunziato, Lucio
    Cerchia, Laura
    [J]. PLOS ONE, 2009, 4 (08):
  • [4] Regulation of microglial activities by glial cell line derived neurotrophic factor
    Chang, YP
    Fang, KM
    Lee, TI
    Tzeng, SF
    [J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 2006, 97 (03) : 501 - 511
  • [5] Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes
    Chen, P-S
    Peng, G-S
    Li, G.
    Yang, S.
    Wu, X.
    Wang, C-C
    Wilson, B.
    Lu, R-B
    Gean, P-W
    Chuang, D-M
    Hong, J-S
    [J]. MOLECULAR PSYCHIATRY, 2006, 11 (12) : 1116 - 1125
  • [6] Microglia of Rat Ventral Midbrain Recovers Its Resting State Over Time In Vitro: Let Microglia Rest Before Work
    Cristovao, Ana Clara
    Saavedra, Ana
    Fonseca, Carla Pais
    Campos, Filipa
    Duarte, Emilia Pedrosa
    Baltazar, Graca
    [J]. JOURNAL OF NEUROSCIENCE RESEARCH, 2010, 88 (03) : 552 - 562
  • [7] Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease
    DeWitt, DA
    Perry, G
    Cohen, M
    Doller, C
    Silver, J
    [J]. EXPERIMENTAL NEUROLOGY, 1998, 149 (02) : 329 - 340
  • [8] Mechanisms Underlying Inflammation in Neurodegeneration
    Glass, Christopher K.
    Saijo, Kaoru
    Winner, Beate
    Marchetto, Maria Carolina
    Gage, Fred H.
    [J]. CELL, 2010, 140 (06) : 918 - 934
  • [9] Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system
    Godbout, JP
    Chen, J
    Abraham, J
    Richwine, AF
    Berg, BM
    Kelley, KW
    Johnson, RW
    [J]. FASEB JOURNAL, 2005, 19 (07) : 1329 - +
  • [10] Gyarfas T., 2009, CELL MOL NEUROBIOL, P30