Abstract
After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar, once the acute phase of the injury has passed. The pleiotropic cytokine interleukin-6 (IL-6) is secreted immediately after injury and regulates scar formation; however, little is known about the role of IL-6 in the sub-acute phases of SCI. Interestingly, IL-6 also promotes axon regeneration, and therefore its induction in reactive astrocytes may improve regeneration after SCI. We found that IL-6 is expressed by astrocytes and neurons one week post-injury and then declines. Using primary cultures of rat astrocytes we delineated the molecular mechanisms that regulate IL-6 expression and secretion. IL-6 expression requires activation of p38 and depends on NF-κB transcriptional activity. Activation of these pathways in astrocytes occurs when the PI3K-mTOR-AKT pathway is inhibited. Furthermore, we found that an increase in cytosolic calcium concentration was necessary for IL-6 secretion. To induce IL-6 secretion in astrocytes, we used torin2 and rapamycin to block the PI3K-mTOR pathway and increase cytosolic calcium, respectively. Treating injured animals with torin2 and rapamycin for two weeks, starting two weeks after injury when the scar has been formed, lead to a modest effect on mechanical hypersensitivity, limited to the period of treatment. These data, taken together, suggest that treatment with torin2 and rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI.
Highlights
The physiological outcome after spinal cord injury (SCI) is the result of a coordinated response of many cell types
When the different regions in the spinal cord sections were examined, IL-6 expression increased in the gray matter and in the dorsal column, but no changes were detectable in other regions (Figure 1C (III))
We found that when astrocytes were treated with torin2/1+rapamycin, IL-6 was detected in the supernatant, but only when torin2 was used at 1 mM, the concentration at which PI3K and PDK1-AKT pathways were inhibited (Figure 6A,C, 4B–C)
Summary
The physiological outcome after spinal cord injury (SCI) is the result of a coordinated response of many cell types. Astrocytes play a key role in the scar formation that follows SCI [1]. During this process, astrocytes interact with microglia and immune cells to isolate and clear damaged tissue and to reestablish normal homeostasis of the spinal cord [2,3]. Interleukin-6 (IL-6) is a pleiotropic cytokine and its effects on SCI depend mostly on the temporal expression and the balance between survival-promoting and pro-inflammatory effects. Following SCI, microglia and macrophages secrete IL-6, which is thought to play a negative role in regeneration by recruiting immune cells to the site of injury and by promoting glial scar formation [6]. IL-6 expression has positive roles in regeneration by promoting synaptic rearrangements, axon sprouting, and reducing tissue loss [7,8]
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