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The Journal of Neuroscience, August 15, 2007, 27(33):8745-8756; doi:10.1523/JNEUROSCI.1002-07.2007

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Neurobiology of Disease
Calcineurin in Reactive Astrocytes Plays a Key Role in the Interplay between Proinflammatory and Anti-Inflammatory Signals

Ana M. Fernandez, Silvia Fernandez, Paloma Carrero, Miguel Garcia-Garcia, and Ignacio Torres-Aleman

Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain

Correspondence should be addressed to I. Torres-Aleman, Cajal Institute, Consejo Superior de Investigaciones Científicas, Avenida Dr. Arce 37, 28002 Madrid, Spain. Email: torres{at}cajal.csic.es

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- (TNF-) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor B (NFB) 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 NFB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF- 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.

Key words: calcineurin; neuroinflammation; astrocytes; inflammatory cytokines; insulin-like growth factor I; neuronal death

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Received Nov. 8, 2006; revised May 29, 2007; accepted June 14, 2007.

Correspondence should be addressed to I. Torres-Aleman, Cajal Institute, Consejo Superior de Investigaciones Científicas, Avenida Dr. Arce 37, 28002 Madrid, Spain. Email: torres{at}cajal.csic.es

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