title: Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling.
abstract: 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.
authors.affiliation: Division of Experimental Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Leibinger
authors.affiliation: Division of Experimental Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Andreadaki
authors.affiliation: Division of Experimental Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Gobrecht
authors.affiliation: Division of Experimental Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Levin
authors.affiliation: Division of Experimental Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Diekmann
authors.affiliation: Division of Experimental Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009186:Myelin Sheath / Q000378:metabolism*; D009416:Nerve Regeneration; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D050822:Cytokine Receptor gp130; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human