Interleukin-6 contributes to CNS axon regeneration upon inflammatory stimulation

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.

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

“…2,5,[17][18][19]36,37 However, these effects appear rather moderate in comparison to genetic depletion of SOCS3 or PTEN, which act as cell-intrinsic inhibitors of cytokine-induced signaling pathways. 6,[21][22][23] Consequently, naive IL-6-type cytokines, released after IS or applied at high and sustained levels, are seemingly insufficient to induce optimal gp130 signaling in injured neurons.…”

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

“…Note that the mice in these experiments were from a Bax WT background to enable direct comparison with the original PTEN deletion data (Park et al, 2008); however, this means that possible survivalpromoting effects of the mutant alleles cannot be excluded. The extent of regeneration achieved by direct genetic activation of specific intracellular signaling pathways, including B-RAF, DLK, PI3-kinase-mTOR, KLF, and JAK-STAT pathways Yan et al, 2009;Park et al, 2010;Blackmore et al, 2012;Shin et al, 2012;Lang et al, 2013), compares favorably with what has been reported for application of growth factors such as NGF, BDNF, GDNF, and CNTF (Lykissas et al, 2007;Zhang et al, 2009;Allen et al, 2013;Leibinger et al, 2013). Growth factors as promoters of regeneration are hobbled by two major issues.…”

Revisiting the role of erythropoietin for treatment of ocular disorders

“…41 The complex binding of IL-6 to the receptor requires further association with glycoprotein 130 (gp130) before generating a downstream signal transduction. 42 Recently, Leibinger et al 43 found that optic nerve injury triggered upregulation of IL-6 and the binding of IL-6 to its receptor on the retina, via activation of JAK/STAT3 transduction pathway, ultimately promoted neurite outgrowth and prolonged survivability of mature retinal ganglion cells in Table 2. Clinical application of EPO for treatment of ocular disorders SL Shirley Ding et al culture.…”