Caspase-11 mediates ischemia-induced astrocyte death: involvement of endoplasmic reticulum stress and C/EBP homologous protein.

Abstract

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.

• Authors: Noelia Fradejas, María Dolores Pastor, Miguel Burgos, Rudi Beyaert, Pedro Tranque, Soledad Calvo
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 88 Issue 5 Pg. 1094-105 (Apr 2010) ISSN: 1097-4547 [Electronic] United States
• PMID: 19890920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2009 Wiley-Liss, Inc.

Chemical References

• Caspase Inhibitors
• RNA, Messenger
• Tunicamycin
• Transcription Factor CHOP
• Thapsigargin
• Casp4 protein, rat
• Caspases

Topics

• Animals
• Apoptosis (physiology)
• Astrocytes (metabolism, pathology)
• Brain Ischemia (metabolism, physiopathology)
• Caspase Inhibitors
• Caspases (genetics, metabolism)
• Cells, Cultured
• Disease Models, Animal
• Endoplasmic Reticulum (metabolism, pathology)
• Genetic Vectors (pharmacology)
• RNA Interference (physiology)
• RNA, Messenger (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• Stress, Physiological (physiology)
• Thapsigargin (toxicity)
• Transcription Factor CHOP (genetics, metabolism)
• Transfection (methods)
• Tunicamycin (toxicity)