Interleukin-6 Secretion by Astrocytes Is Dynamically Regulated by PI3K-mTOR-Calcium Signaling

PLoS ONE, 2014 · DOI: 10.1371/journal.pone.0092649 · Published: March 25, 2014

Simple Explanation

After spinal cord injury, astrocytes become reactive and form a glial scar, which inhibits regeneration. Interleukin-6 (IL-6) regulates scar formation and promotes axon regeneration. The study found that IL-6 is expressed by astrocytes and neurons after injury, and its expression requires activation of p38 and depends on NF-kB transcriptional activity. Inhibition of the PI3K-mTOR-AKT pathway in astrocytes, along with an increase in cytosolic calcium concentration, is necessary for IL-6 secretion, potentially contributing to reduced mechanical hypersensitivity after SCI.

Study Duration

6 weeks

Participants

Female rats (220 g)

Evidence Level

Not specified

Key Findings

1
IL-6 is expressed by astrocytes, neurons, and microglia/macrophages in the spinal cord after contusion injury.
2
mTORC1 activity is negatively correlated with IL-6 expression in reactive astrocytes after SCI.
3
Inhibition of the PI3K-mTOR pathway and increased cytosolic calcium are necessary for IL-6 secretion by astrocytes.

Research Summary

This study investigates the regulation of Interleukin-6 (IL-6) secretion by astrocytes after spinal cord injury (SCI). It identifies the PI3K-mTOR-Calcium signaling pathway as a key regulator of IL-6 expression and secretion in astrocytes. The research demonstrates that IL-6 expression requires activation of p38 and depends on NF-kB transcriptional activity, while IL-6 secretion necessitates inhibition of the PI3K-mTOR pathway and increased cytosolic calcium levels. Treatment of injured animals with torin2 and rapamycin, targeting the PI3K-mTOR pathway and calcium levels respectively, showed a temporary reduction in mechanical hypersensitivity, suggesting a potential therapeutic strategy for SCI recovery.

Practical Implications

Therapeutic Target Identification

The identification of the PI3K-mTOR-Calcium pathway as a regulator of IL-6 secretion provides a potential therapeutic target for modulating astrocyte activity after SCI.

Drug Combination Strategy

The study suggests that a combination therapy targeting both the PI3K-mTOR pathway (e.g., with torin2) and intracellular calcium levels (e.g., with rapamycin) may be more effective in promoting IL-6 release and potentially improving recovery after SCI.

Temporal Treatment Considerations

The findings suggest that timing of treatment is critical, with IL-6 induction potentially being most beneficial during specific phases of SCI, such as after the acute phase but before scar maturation.

Study Limitations

1
The study focuses on mechanical hypersensitivity as the primary outcome measure, and further research is needed to assess the impact on other functional outcomes after SCI.
2
The systemic administration of drugs makes it difficult to determine whether the observed effects are specifically mediated by astrocytes in the spinal cord or by other cell types or systemic factors.
3
The treatment with torin2 and rapamycin only resulted in a temporary improvement in mechanical hypersensitivity.

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