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. Copyright © 2007 Society for Neuroscience.
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Fernandez, A. M., Fernandez, S., Carrero, P., Garcia-Garcia, M., & Torres-Aleman, I. (2007). Calcineurin in reactive astrocytes plays a key role in the interplay between proinflammatory and anti-inflammatory signals. Journal of Neuroscience, 27(33), 8745–8756. https://doi.org/10.1523/JNEUROSCI.1002-07.2007