Caspase signalling controls microglia activation and neurotoxicity

被引:486
作者
Burguillos, Miguel A. [1 ,2 ,3 ,4 ]
Deierborg, Tomas [4 ]
Kavanagh, Edel [1 ]
Persson, Annette [5 ]
Hajji, Nabil [1 ]
Garcia-Quintanilla, Albert [6 ]
Cano, Josefina [2 ,3 ]
Brundin, Patrik [4 ]
Englund, Elisabet [5 ]
Venero, Jose L. [2 ,3 ]
Joseph, Bertrand [1 ]
机构
[1] Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden
[2] Univ Seville, Dept Bioquim & Biol Mol, Fac Farm, E-41012 Seville, Spain
[3] Inst Biomed Sevilla, Seville 41012, Spain
[4] Wallenberg Neurosci Ctr, Dept Expt Med Sci, Neuronal Survival Unit, S-22184 Lund, Sweden
[5] Univ Lund Hosp, Div Neuropathol, Dept Pathol, S-22185 Lund, Sweden
[6] Univ Seville, Serv Biol, CITIUS, Ctr Invest Tecnol & Innovac, E-41012 Seville, Spain
基金
瑞典研究理事会;
关键词
KINASE-C-DELTA; NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; BLOOD-BRAIN-BARRIER; PARKINSONS-DISEASE; DOPAMINERGIC-NEURONS; ALZHEIMERS-DISEASE; ENDOTOXIC-SHOCK; NITRIC-OXIDE; CELL-DEATH;
D O I
10.1038/nature09788
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-delta-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
引用
收藏
页码:319 / U214
页数:7
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