Interleukin-1beta-dependent signaling between astrocytes and neurons depends critically on astrocytic calcineurin/NFAT activity.
Interleukin-1beta (IL-1beta) and the Ca(2+)/calmodulin-dependent protein phosphatase, calcineurin, have each been shown to play an important role in neuroinflammation. However, whether these signaling molecules interact to coordinate immune/inflammatory processes and neurodegeneration has not been investigated. Here, we show that exogenous application of IL-1beta (10 ng/ml) recruited calcineurin/NFAT (nuclear factor of activated T cells) activation in primary astrocyte-enriched cultures within minutes, through a pathway involving IL-1 receptors and L-type Ca(2+) channels. Adenovirus-mediated delivery of the NFAT inhibitor, VIVIT, suppressed the IL-1beta-dependent induction of several inflammatory mediators and/or markers of astrocyte activation, including tumor necrosis factor alpha, granulocyte/macrophage colony-stimulating factor, and vimentin. Expression of an activated form of calcineurin in one set of astrocyte cultures also triggered the release of factors that, in turn, stimulated NFAT activity in a second set of "naive" astrocytes. This effect was prevented when calcineurin-expressing cultures co-expressed VIVIT, suggesting that the calcineurin/NFAT pathway coordinates positive feedback signaling between astrocytes. In the presence of astrocytes and neurons, 48-h delivery of IL-1beta was associated with several excitotoxic effects, including NMDA receptor-dependent neuronal death, elevated extracellular glutamate, and hyperexcitable synaptic activity. Each of these effects were reversed or ameliorated by targeted delivery of VIVIT to astrocytes. IL-1beta also caused an NFAT-dependent reduction in excitatory amino acid transporter levels, indicating a possible mechanism for IL-1beta-mediated excitotoxicity. Taken together, the results have potentially important implications for the propagation and maintenance of neuroinflammatory signaling processes associated with many neurodegenerative conditions and diseases.
Department of Molecular and Biomedical Pharmacology, Graduate Center for Gerontology, University of Kentucky, Lexington, Kentucky 40536, USA.
Michelle A
MA
Sama
Diana M
DM
Mathis
Jennifer L
JL
Furman
Hafiz Mohmmad
HM
Abdul
Irina A
IA
Artiushin
Susan D
SD
Kraner
Christopher M
CM
Norris
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000187:drug effects; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport; D011506:Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D020746:Calcium Channels, L-Type; D050491:Glutamate Plasma Membrane Transport Proteins; D053583:Interleukin-1beta; D050778:NFATC Transcription Factors; D011506:Proteins; D019703:Calcineurin