Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuroprotective.
Astrocytes express high levels of connexin43, a protein that forms two types of channels: gap junction channels for direct intercellular communication, and hemichannels for exchanges with the extracellular space. Inflammation induces connexin43 hemichannel activation, which has been proposed to be involved in neuroglial interactions. Here, we investigated the contribution of connexin43 to NMDA-induced excitotoxicity in neuron/astrocyte co-cultures, after treatment with a pro-inflammatory cytokine mixture, containing TNF-alpha and IL1-beta (Mix), that stimulated astroglial connexin43 hemichannel activity. Interestingly, NMDA treatment induced a higher amount of neurotoxicity in Mix-treated co-cultures than in untreated ones, whereas this extent of neurotoxicity was absent in enriched neuron cultures or in co-cultures with connexin43 knock-out astrocytes. Furthermore, application of connexin43 hemichannel blockers or a synthetic cannabinoid prevented the Mix-induced potentiated NMDA neurotoxicity. Altogether, these data demonstrate that inflammation-induced astroglial hemichannel activation plays a critical role in neuronal death and suggest a neuroprotective role of connexin43 hemichannel blockade.
Froger
Nicolas
N
INSERM U840, Collège de France, 11 Place Marcelin Berthelot, 75231 Paris, Cedex 05, France. nicolas.froger@inserm.fr
Orellana
Juan A
JA
Calvo
Charles-Felix
CF
Amigou
Edwige
E
Kozoriz
Michael G
MG
Naus
Christian C
CC
Sáez
Juan C
JC
Giaume
Christian
C
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D018031:Connexin 43 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018031:Connexin 43; D016207:Cytokines; D005456:Fluorescent Dyes; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate