ABSTRACT
Following central nervous system injury, astrocytes rapidly respond by undergoing a stereotypical pattern of molecular and morphological alterations termed "reactive" astrogliosis. We have reported previously that metallothioneins (MTs) are rapidly expressed by reactive astrocytes and that their secretion and subsequent interaction with injured neurons leads to improved neuroregeneration. We now demonstrate that exogenous MT induces a reactive morphology and elevated GFAP expression in cultured astrocytes. Furthermore, these astrogliotic hallmarks were mediated via JAK/STAT and RhoA signalling pathways. However, rather than being inhibitory, MT induced a form of astrogliosis that was permissive to neurite outgrowth and which was associated with decreased chondroitin sulphate proteoglycan (CSPG) expression. The results suggest that MT has an important role in mediating permissive astrocytic responses to traumatic brain injury.
Subject(s)
Astrocytes/drug effects , Metallothionein/pharmacology , Regeneration/drug effects , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , rhoA GTP-Binding Protein/metabolism , Animals , Animals, Newborn , Astrocytes/physiology , Axons/drug effects , Axons/physiology , Cells, Cultured , Cerebral Cortex/cytology , Chondroitin Sulfate Proteoglycans/genetics , Chondroitin Sulfate Proteoglycans/metabolism , Enzyme Inhibitors/pharmacology , Glial Fibrillary Acidic Protein/metabolism , Metallothionein/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/cytology , Neurons/physiology , Rats , Transforming Growth Factor beta1/pharmacologyABSTRACT
The kynurenine pathway has been implicated as a major component of the neuroinflammatory response to brain injury and neurodegeneration. We found that the neurotoxic kynurenine pathway intermediate quinolinic acid (QUIN) is rapidly expressed, within 24 h, by reactive microglia following traumatic injury to the rodent neocortex. Furthermore, administration of the astrocytic protein metallothionein attenuated this neuroinflammatory response by reducing microglial activation (by approximately 30%) and QUIN expression. The suppressive effect of MT was confirmed upon cultured cortical microglia, with 1 mug/ml MT almost completely blocking interferon-gamma induced activation of microglia and QUIN expression. These results demonstrate the neuroimmunomodulatory properties of MT, which may have therapeutic applications for the treatment of traumatic brain injury.