Pro‐regenerative properties of cytokine‐activated astrocytes

Abstract

The prevailing view of the astrocytic response to injury is that reactive astrocytes impede the regenerative process by forming scar tissue. As the levels of many cytokines dramatically increase following CNS insult and as this increase in cytokine expression precedes the production of the glial scar, a longstanding view has been that cytokines diminish neuronal survival and regeneration by stimulating the formation of astrogliotic scar tissue. However, there is a wealth of data indicating that cytokines 'activate' astrocytes, and that cytokinestimulated astrocytes can promote the recovery of CNS function. Supporting evidence demonstrates that cytokine-activated astrocytes produce energy substrates and trophic factors for neurons and oligodendrocytes, act as free radical and excess glutamate scavengers, actively restore the blood-brain barrier, promote neovascularization, restore CNS ionic homeostasis, promote remyelination and also stimulate neurogenesis from neural stem cells. Accordingly, a re-assessment of cytokineactivated astrocytes is necessary. Here, we review studies that promote the thesis that cytokines elicit potent neuroprotective and regenerative responses from astrocytes. Keywords: ciliary neurotrophic factor, gliosis, interleukin-1, microglia. J. Neurochem. (2004) 89, 1092-1100. Astrocytes are the major support cells of the CNSAstrocytes are dynamic cells that maintain homeostasis in the undamaged CNS. Astrocytes express numerous receptors that enable them to respond to virtually all known neuroactive compounds, including neurotransmitters, neuropeptides, growth factors, cytokines, small molecules and toxins. These receptors enable astrocytes to not only participate in signal processing, but to function as sentinels. Astrocytes also establish and maintain CNS boundaries, including the blood-brain barrier (BBB) and the glial limitans, through interactions with endothelial and leptomeningeal cells. Given their important roles in establishing and maintaining CNS homeostasis, an adaptive response by astrocytes to tissue damage should be expected. Indeed, when astrocytes sense that the homeostasis of the brain or spinal cord has been disrupted, their metabolic activity increases, as well as their production of growth and trophic factors; thus endowing them with a greater capacity to protect other brain cells from energy depletion, toxic-free radicals, ammonia, metals and calcium overload. Additionally, after injury, cytokine-activated astrocytes promote the reformation of essential barriers and reestablishment of CNS ionic homeostasis.

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…Increased levels of GFAP may also indicate astrocyte activation in our cell cultures by chronic CXCL10 treatment. Activated astrocytes are known to produce soluble trophic and growth factors, and immunomodulatory cytokines that enhance the survival of adjacent neurons and glia in the likely attempt to preserve tissue integrity (Liberto et al, 2004;Ridet et al, 1997;Schwartz et al, 1993). Therefore, effects of chronic CXCL10 on hippocampal neurons observed in our studies may also involve in direct pathways through activation of astrocytes and subsequent secretion of growth factors, cytokines and chemokines and act on the neurons.…”

The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

“…As yet it is completely unexamined how the interactions described by Zipp and colleagues versus by Liu et al may be coordinately regulated or even simultaneously cross-regulate final T cell function and neuronal viability [18]! While direct neuronal: T cell interactions are still incompletely characterized and their biological relevance still debated, neuronal regulation of gliosis has been widely examined and is recognized to play a major role in eliciting protective versus destructive inflammatory responses [21][22][23][24]. Indeed astrocytes and microglia appear highly specialized to detect and to respond to neuronal health and activity.…”

“…Astrocytes are one of the two primary types of macroglia [21][22][23]. They comprise nearly 35% of the total CNS cell population and like microglia are found in all regions of the CNS.…”

“…With these caveats in mine, astrogliosis and astroglial scar formation (usually monitored only by increased GFAP immunoreactivity) have been found to be nearly as common a response to CNS injury and dysfunction as microgliosis [23]. As yet, the adaptive consequences of astroglial scar formation are still a subject of debate.…”

“…For example, astrocytes play a critical role in modulating glutamate levels in the extracellular space contributing both to the functional neuronal synapse and to the prevention of glutamate-induced excitotoxic cell death of neurons [23,27,28]. In addition, astrocyte endfeet are a key component of the blood brain barrier (BBB) [29][30][31].…”