Calcineurin in reactive astrocytes plays a key role in the interplay between proinflammatory and anti-inflammatory signals.
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-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.
Fernandez
Ana M
AM
Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Fernandez
Silvia
S
Carrero
Paloma
P
Garcia-Garcia
Miguel
M
Torres-Aleman
Ignacio
I
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000150:complications; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
D019703:Calcineurin; D005904:Glial Fibrillary Acidic Protein; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase
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