Abstract
Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons and undergo apoptosis after axotomy. Inflammatory stimulation (IS) in the eye mediates neuroprotection and induces axon regeneration into the injured optic nerve. Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) have been identified as key mediators of these effects. Here, we investigated the role of interleukin-6 (IL-6), another member of the glycoprotein 130-activating cytokine family, as additonal contributing factor. Expression of IL-6 was markedly induced in the retina upon optic nerve injury and IS, and mature RGCs expressed the IL-6 receptor. Treatment of cultured RGCs with IL-6 or specific IL-6 receptor agonist, significantly increased neurite outgrowth janus kinase/signal transducers and activators of transcription-3 (JAK/STAT3) and phosphatidylinositide 3-kinase/protein kinase B (PI3K/Akt) dependently. Moreover, IL-6 reduced myelin, but not neurocan-mediated growth inhibition mammalian target of rapamycin (mTOR) dependently in cultured RGCs. In vivo, intravitreal application of IL-6 transformed RGCs into a regenerative state, enabling axon regeneration beyond the lesion site of the optic nerve. On the other hand, genetic ablation of IL-6 in mice significantly reduced IS-mediated myelin disinhibition and axon regeneration in the optic nerve. Therefore, IL-6 contributes to the beneficial effects of IS and its disinhibitory effect adds an important feature to the effects of so far identified IS-mediating factors. Consequently, application of IL-6 or activation of its receptor might provide suitable strategies for enhancing optic nerve regeneration.
Highlights
Regenerative failure of injured axons has been related to inhibitory proteins that are associated with central nervous system (CNS) myelin or the glial scar[1,2] and to an insufficient intrinsic ability of mature central neurons to re-grow injured axons.[3,4,5] retinal ganglion cells (RGCs) do not normally regenerate axons after optic nerve injury, but, instead, undergo apoptotic cell death.[6]
We measured IL-6 expression in retinas derived from untreated rats or from animals that were subjected to optic nerve crush (ONC), inflammatory stimulation (IS) or ONC þ IS using quantitative realtime PCR (Figure 1a)
Consistent with mRNA levels, IL-6 protein was detectable in retinal lysates 7 days after surgery with significant higher amounts after ONC þ IS as determined by ELISA
Summary
Regenerative failure of injured axons has been related to inhibitory proteins that are associated with CNS myelin or the glial scar[1,2] and to an insufficient intrinsic ability of mature central neurons to re-grow injured axons.[3,4,5] retinal ganglion cells (RGCs) do not normally regenerate axons after optic nerve injury, but, instead, undergo apoptotic cell death.[6]. RGCs are able to survive injury and to re-grow axons into the inhibitory environment of the lesioned optic nerve.[7,8,9,10,11] IS exerts neuroprotective, axon growth promoting and significant disinhibitory effects. IS can be induced either by lens injury (LI)[7,8,12,13,14] or by intravitreal application of crystallins[15] or Toll-like receptor 2 agonists.[16,17,18] Astrocyte-derived ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) have been identified as essential mediators of the neuroprotective and axon growth-stimulating effects of IS.[16,19,20,21] neither CNTF nor LIF exert disinhibitory effects, suggesting that additional factors contribute to ISmediated optic nerve regeneration.[22,23]. The effects of Received 07.1.13; revised 26.2.13; accepted 1.3.13; Edited by A Verkhratsky
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