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Caspase‐11 mediates ischemia‐induced astrocyte death: Involvement of endoplasmic reticulum stress and C/EBP homologous protein
Author(s) -
Fradejas Noelia,
Pastor María Dolores,
Burgos Miguel,
Beyaert Rudi,
Tranque Pedro,
Calvo Soledad
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22280
Subject(s) - endoplasmic reticulum , unfolded protein response , astrocyte , microbiology and biotechnology , ischemia , stim1 , homologous chromosome , chemistry , biology , neuroscience , medicine , biochemistry , central nervous system , gene
Astrocytes are essential cells for maintaining brain integrity. We have recently shown that the transcription factor C/EBP homologous protein (CHOP), associated with endoplasmic reticulum (ER) stress, plays a key role in the astrocyte death induced by ischemia. Meanwhile, mediators of apoptosis downstream of CHOP in the ER stress‐dependent pathway remain to be elucidated. Our aim in this work was to determine whether caspase‐11, able to activate apoptotic and proinflammatory pathways, is implicated in ER stress‐dependent astrocyte death in ischemic conditions. According to our results, caspase‐11 is up‐regulated in primary astrocyte cultures following either oxygen and glucose deprivation (OGD) or treatment with the ER‐stress inducers thapsigargin and tunicamycin. Moreover, these same stimuli increased caspase‐11 mRNA levels and luciferase activity driven by a caspase‐11 promoter, indicating that caspase‐11 is regulated at the transcriptional level. Our data also illustrate the involvement of ER stress‐associated CHOP in caspase‐11 regulation, insofar as CHOP overexpression by means of an adenoviral vector caused a significant raise in caspase‐11. In turn, caspase‐11 suppression with siRNA rescued astrocytes from OGD‐ and ER stress‐induced death, supporting the idea that caspase‐11 is responsible for the deleterious effects of ischemia on astrocytes. Finally, inhibition of caspase‐1 and caspase‐3 significantly reduced astrocyte death, which indicates that these proteases act as death effectors of caspase‐11. In conclusion, our work contributes to clarifying the pathways leading to astrocyte death in response to ischemia by defining caspase‐11 as a key mediator of the ER stress response acting downstream of CHOP. © 2009 Wiley‐Liss, Inc.