Caspase-11 mediates ischemia-induced astrocyte death: involvement of endoplasmic reticulum stress and C/EBP homologous protein.
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.
Fradejas
Noelia
N
Departamento de Ciencias Médicas and Centro Regional de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain.
Pastor
María Dolores
MD
Burgos
Miguel
M
Beyaert
Rudi
R
Tranque
Pedro
P
Calvo
Soledad
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005822:Genetic Vectors / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D019284:Thapsigargin / Q000633:toxicity; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014415:Tunicamycin / Q000633:toxicity
D061945:Caspase Inhibitors; D012333:RNA, Messenger; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D019284:Thapsigargin; C491071:Casp4 protein, rat; D020169:Caspases