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Caspase signalling controls microglia activation and neurotoxicity.

Burguillos Garcia, Miguel LU ; Deierborg, Tomas LU ; Kavanagh, Edel; Persson, Annette LU ; Hajji, Nabil; Garcia-Quintanilla, Albert; Cano, Josefina; Brundin, Patrik LU ; Englund, Elisabet LU and Venero, Jose L, et al. (2011) In Nature 472. p.214-319
Abstract
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)-δ-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... (More)
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)-δ-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. (Less)
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Nature
volume
472
pages
214 - 319
publisher
Nature Publishing Group
external identifiers
  • wos:000289724600033
  • pmid:21389984
  • scopus:79955485064
ISSN
0028-0836
DOI
10.1038/nature09788
language
English
LU publication?
yes
id
d043360b-c18e-48bd-808a-5cf577cc898d (old id 1884133)
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http://www.ncbi.nlm.nih.gov/pubmed/21389984?dopt=Abstract
date added to LUP
2011-04-01 14:49:19
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2017-11-19 04:16:14
@article{d043360b-c18e-48bd-808a-5cf577cc898d,
  abstract     = {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)-δ-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.},
  author       = {Burguillos Garcia, Miguel and Deierborg, Tomas and Kavanagh, Edel and Persson, Annette and Hajji, Nabil and Garcia-Quintanilla, Albert and Cano, Josefina and Brundin, Patrik and Englund, Elisabet and Venero, Jose L and Joseph, Bertrand},
  issn         = {0028-0836},
  language     = {eng},
  pages        = {214--319},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Caspase signalling controls microglia activation and neurotoxicity.},
  url          = {http://dx.doi.org/10.1038/nature09788},
  volume       = {472},
  year         = {2011},
}