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

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.

The P2X7 receptor links mechanical strain to cytokine IL‐6 up‐regulation and release in neurons and astrocytes

“…The vesicular release of IL‐6 from spinal cord is calcium dependent (Codeluppi et al . ), and the time course of the IL‐6 release above implies the signaling mechanisms are distinct from those involved in transcriptional up‐regulation. While the increased expression of IL‐6 would provide more IL‐6 for release upon later stimulation, this complex positive feedback pathway was not investigated in this study.…”

“…3g). Cytokine release in many cell types is mediated by increases in intracellular calcium; for example, the release of IL-6 from spinal cord astrocytes is calcium dependent (Codeluppi et al 2014). To confirm optic nerve head astrocytes experience a rise in calcium upon swelling, levels were monitored with indicator Fura-2.…”

Manganese-enhanced MRI depicts a reduction in brain response to nociception by mTOR inhibition in chronic pain rats

“…These results indicate that the inhibitory effect of mTOR signaling was not signi cantly different in response to similar visual cues. Recent studies have suggested that mTOR signaling may be involved in the initiation of pain perception [15,19], which could effectively reduce chronic pain through inhibition of mTOR [43,44]. However, the amount of research on how pain is controlled regarding the regulation of mTOR is still insu cient.…”

“…The activation of mTOR regulates protein synthesis and in uences a wide range of physiological and pathological states by phosphorylating downstream effectors [12,17,18]. In this study, the mTOR selective inhibitors known as Torin1 [19,20] and XL388 [21] were used to modulate the mTOR regulator. Each agent has highly potent and ATP-competitive mTOR inhibitory effects.…”

Heme and hemoglobin suppress amyloid β–mediated inflammatory activation of mouse astrocytes

“…The PI3K/Akt pathway is of particular interest because of its known role in modulating autophagic clearance of A␤ in neurons (58) and because of its known ability to inhibit M1 macrophage polarization (59), which is linked to expression of scavengers receptors, including CD36 (60). Further, this pathway is important to astrocyte immune function, as it is involved in regulating astrocyte viability, migration, autophagy, and production of cytokines and inflammatory mediators (61)(62)(63)(64)(65).…”