Long-distance axonal regeneration induced by CNTF gene transfer is impaired by axonal misguidance in the injured adult optic nerve

Pernet, Vincent; Joly, Sandrine; Dalkara, Deniz; Jordi, Noémie; Schwarz, Olivia; Christ, Frauke; Schaffer, David V.; Flannery, John G.; Schwab, Martin E.

doi:10.1016/j.nbd.2012.11.011

Cited by 113 publications

(132 citation statements)

References 40 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…With respect to the development of a potential therapeutic treatment, this application scheme would be advantageous compared to previous studies deploying AAV-transductions for cytokine expression 1-3 weeks prior to injury. [17][18][19] At first, we analyzed potential neuroprotective effects of hIL-6 expression in comparison to AAV-GFP transduction as well as inflammatory stimulation (IS) and conditional PTEN knockout, two treatments reportedly protecting RGCs from injury-induced cell death. 7,9 Three weeks after ONC, only ~20% of βIII-tubulin-positive RGCs survived in control-injected retinae (353 ± 26 versus 1736 ± 45 RGCs/mm 2 in uninjured retinae), while 529 ± 21 RGCs/mm 2 were quantified in IS-treated retinae (Figure 6b,c).…”

Section: Strong and Sustained Activation Of Gp130 Signaling In Vivomentioning

confidence: 99%

“…5,16 Similarly, application of exogenous CNTF is neuroprotective and stimulates axon regeneration in the injured optic nerve, particularly upon continuous release from virally transduced cells. [16][17][18][19][20] However, cytokine-induced signaling is normally attenuated via intracellular negative feedback loops. For instance, PTEN inhibits PI3K activity, while SOCS3 compromises JAK/ STAT3 pathway activation.…”

Section: Introductionmentioning

confidence: 99%

“…[23][24][25] However, this approach is unfavorable as therapeutic treatment, since it requires neuronal transduction weeks prior to CNS injury and might increase the risk of cancer development post-treatment. [17][18][19] Instead of genetically deleting intracellular inhibitors, we hypothesized that it might be possible to boost axon regeneration by directly enhancing the cytokine-induced stimulus. In order to elicit a cellular response, CNTF and IL-6 first need to bind to their respective high affinity, but nonsignaling α-receptors (CNTFRα, IL-6Rα), which then recruit further signaling receptor subunits.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Retinal ganglion cells (RGCs) do not normally regenerate injured axons, but die upon axotomy. Although IL-6-like cytokines are reportedly neuroprotective and promote optic nerve regeneration, their overall regenerative effects remain rather moderate. Here, we hypothesized that direct activation of the gp130 receptor by the designer cytokine hyper-IL-6 (hIL-6) might induce stronger RGC regeneration than natural cytokines. Indeed, hIL-6 stimulated neurite growth of adult cultured RGCs with significantly higher efficacy than CNTF or IL-6. This neurite growth promoting effect could be attributed to stronger activation of the JAK/STAT3 and PI3K/AKT/mTOR signaling pathways and was also observed in peripheral dorsal root ganglion neurons. Moreover, hIL-6 abrogated axon growth inhibition by central nervous system (CNS) myelin. Remarkably, continuous hIL-6 expression upon RGC-specific AAV transduction after optic nerve crush exerted stronger axon regeneration than other known regeneration promoting treatments such as lens injury and PTEN knockout, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Combination of hIL-6 with RGC-specific PTEN knockout further enhanced optic nerve regeneration. Therefore, direct activation of gp130 signaling might be a novel, clinically applicable approach for robust CNS repair.

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Section: Discussionmentioning

confidence: 99%

Section: Strong and Sustained Activation Of Gp130 Signaling In Vivomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…16,27 Similarly, application of exogenous CNTF, LIF, and IL-6 mediates neuroprotection and stimulates axon regeneration in RGC cultures as well as the injured optic nerve in vivo, particularly upon continuous release from virally transduced cells. 26,[28][29][30][31] CNTF, LIF, and IL-6 belong to the family of interleukin-6 (IL-6)-type cytokines activating the signal transducing receptor glycoprotein 130 (gp130) (Figure 1), 32 which in the adult retina is mainly expressed in RGCs. 33 LIF requires direct interaction with the LIF-receptor (LIFR) to form a signaling complex with gp130.…”

Section: Introductionmentioning

confidence: 99%

Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration

Fischer

2016

Eye

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Mature retinal ganglion cells (RGCs) normally fail to regenerate injured axons and die soon after optic nerve injury. Research over the last two decades has demonstrated that application of IL-6-like cytokines or activation of respective downstream signaling pathways promote neuroprotection and optic nerve regeneration. However, the overall beneficial effects of natural cytokines remain usually rather moderate, possibly due to intrinsic signaling pathway inhibitors, such as PTEN or SOCS3, or a limited expression of specific cytokine receptors in RGCs. It was recently demonstrated that directly targeting the gp130 receptor, a common signalling receptor of all IL-6-like cytokines, induces stronger RGC axon regeneration in vitro and in vivo than other known growth-promoting treatments such as inflammatory stimulation or PTEN knockout. Remarkably, continuous expression of hyper-IL-6 (hIL-6) upon intravitreal AAV injection after nerve injury enables long-distance axon regeneration, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Thus, AAV-mediated hIL-6 delivery is so far one of the strongest single, post-injury treatments for the promotion of optic nerve regeneration and may be suitable for the development of novel, clinically applicable therapeutic treatments for human patients.

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