PT  - JOURNAL ARTICLE
AU  - Ana M. Fernandez
AU  - Silvia Fernandez
AU  - Paloma Carrero
AU  - Miguel Garcia-Garcia
AU  - Ignacio Torres-Aleman
TI  - Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay between Proinflammatory and Anti-Inflammatory Signals
AID  - 10.1523/JNEUROSCI.1002-07.2007
DP  - 2007 Aug 15
TA  - The Journal of Neuroscience
PG  - 8745--8756
VI  - 27
IP  - 33
4099  - http://www.jneurosci.org/content/27/33/8745.short
4100  - http://www.jneurosci.org/content/27/33/8745.full
SO  - J. Neurosci.2007 Aug 15; 27
AB  - Maladaptive inflammation is a major suspect in progressive neurodegeneration, but the underlying mechanisms are difficult to envisage in part because reactive glial cells at lesion sites secrete both proinflammatory and anti-inflammatory mediators. We now report that astrocytes modulate neuronal resilience to inflammatory insults through the phosphatase calcineurin. In quiescent astrocytes, inflammatory mediators such as tumor necrosis factor-α (TNF-α) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor κB (NFκB) and nuclear factor of activated T-cells (NFAT). However, in reactive astrocytes, local anti-inflammatory mediators such as insulin-like growth factor I also recruit calcineurin but, in this case, to inhibit NFκB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF-α or endotoxins and markedly enhanced neuronal survival. Furthermore, regulated expression of constitutively active calcineurin in astrocytes markedly reduced inflammatory injury in transgenic mice, in a calcineurin-dependent manner. These results suggest that calcineurin forms part of a molecular pathway whereby reactive astrocytes determine the outcome of the neuroinflammatory process by directing it toward either its resolution or its progression.