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

AuthorsFernández García, Ana María ; Fernández, Silvia Venero; Carrero, P.; García-García, Miguel; Torres Alemán, Ignacio
inflammatory cytokines
insulin-like growth factor I
neuronal death
Issue Date2007
PublisherSociety for Neuroscience
CitationJournal of Neuroscience 27 (33): 8745-8756 (2007)
AbstractMaladaptive 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-alpha (TNF-alpha) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor kappaB (NFkappaB) 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 NFkappaB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF-alpha 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
Description12 pages, 7 figures, 1 table,Supplemental Data . - PMID: 17699657 [PubMed - indexed for MEDLINE] Free Article
Publisher version (URL)http://www.jneurosci.org/content/27/33/8745.full.pdf+html
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