Cytokine-induced SOCS expression is inhibited by cAMP analogue: Impact on regeneration in injured retina

Park, Kevin K.; Hu, Ying; Muhling, Jillian; Pollett, Margaret A.; Dallimore, Elizabeth; Turnley, Ann M.; Cui, Qing; Harvey, Alan R.

doi:10.1016/j.mcn.2009.04.002

Cited by 83 publications

(60 citation statements)

References 84 publications

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“…However, oncomodulin expression levels were detected, but not measurably upregulated in the inner eye of mice after optic nerve injury and LI. These data are consistent with previous findings in rats Park et al, 2009) and therefore also argue against a claimed principal role of oncomodulin in mediating the beneficial effects of inflammatory stimulation (Yin et al, 2006;Yin, 2007, 2008;Cui et al, 2009). Furthermore, it should be noted that (1) intravitreal application of antioncomodulin antibodies did not compromise LI effects, (2) oncomodulin alone is insufficient to enhance axon regeneration of mature RGCs in vitro and in vivo and instead requires additional cAMP elevation, and (3) the effects of oncomodulin ϩ cAMP elevation are markedly weaker than those of CNTF alone (Müller et al, 2007Fischer, 2008).…”

Section: Discussionsupporting

confidence: 93%

“…However, macrophage depletion in the eye does not significantly abolish the neuroprotective effects or axon growth-promoting properties of LI . Moreover, expression levels of oncomodulin in the inner eye are low and not significantly elevated after macrophage infiltration Park et al, 2009). In contrast to macrophages, a reduction in the number of activated retinal glia significantly compromised the beneficial results of zymosan (Lorber et al, 2009), and the beneficial effects of LI were stronger correlated with astrocyte/Müller cell activation than with the number of activated macrophages Lorber et al, 2008), suggesting that glial-derived factors are the main mediators of these regenerative effects.…”

Section: Introductionmentioning

confidence: 97%

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Neuroprotective and Axon Growth-Promoting Effects following Inflammatory Stimulation on Mature Retinal Ganglion Cells in Mice Depend on Ciliary Neurotrophic Factor and Leukemia Inhibitory Factor

Leibinger¹,

Müller²,

Andreadaki³

et al. 2009

J. Neurosci.

223

218

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After optic nerve injury retinal ganglion cells (RGCs) normally fail to regenerate axons in the optic nerve and undergo apoptosis. However, lens injury (LI) or intravitreal application of zymosan switch RGCs into an active regenerative state, enabling these neurons to survive axotomy and to regenerate axons into the injured optic nerve. Several factors have been proposed to mediate the beneficial effects of LI. Here, we investigated the contribution of glial-derived ciliary neurotrophic factor (CNTF) to LI-mediated regeneration and neuroprotection using wild-type and CNTF-deficient mice. In wild-type mice, CNTF expression was strongly upregulated in retinal astrocytes, the JAK/STAT3 pathway was activated in RGCs, and RGCs were transformed into an active regenerative state after LI. Interestingly, retinal LIF expression was correlated with CNTF expression after LI. In CNTF-deficient mice, the neuroprotective and axon growth-promoting effects of LI were significantly reduced compared with wild-type animals, despite an observed compensatory upregulation of LIF expression in CNTF-deficient mice. The positive effects of LI and also zymosan were completely abolished in CNTF/LIF double knock-out mice, whereas LI-induced glial and macrophage activation was not compromised. In culture CNTF and LIF markedly stimulated neurite outgrowth of mature RGCs. These data confirm a key role for CNTF in directly mediating the neuroprotective and axon regenerative effects of inflammatory stimulation in the eye and identify LIF as an additional contributing factor.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 97%

Neuroprotective and Axon Growth-Promoting Effects following Inflammatory Stimulation on Mature Retinal Ganglion Cells in Mice Depend on Ciliary Neurotrophic Factor and Leukemia Inhibitory Factor

Leibinger¹,

Müller²,

Andreadaki³

et al. 2009

J. Neurosci.

223

218

View full text Add to dashboard Cite

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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. We therefore tested whether direct stimulation of endogenous gp130 receptors using the designer cytokine hIL-6 might be a superior, therapeutically applicable approach to induce robust signal pathway activation and CNS axon regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, PTEN inhibits PI3K activity, while SOCS3 compromises JAK/ STAT3 pathway activation. 6,21,22 Consequently, removal of these intrinsic brakes, e.g. by PTEN knockout, is sufficient to promote remarkable axon regeneration.…”

Section: Introductionmentioning

confidence: 99%

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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“…59 Co-injection of CNTF with CPT-cAMP reduced CNTF-induced upregulation of suppressor of cytokine signal (SOCS) in both mRNA and protein, suggesting that cytokine-induced regenerative responses could be augmented by cyclic nucleotide in another way. 70 SOCS overexpression may result in an overall reduction of axonal regrowth or even complete regeneration failure of RGC axons. 71 The drug that inhibits cyclic nucleotide phophodiesterase was reported to increase RGC survival possibly through activating PKA signal.…”

mentioning

confidence: 99%

Restoration of optic neuropathy

You¹,

Wu²,

Kuang³

et al. 2017

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Optic neuropathy refers to disorders involving the optic nerve (ON). Any damage to ON or ON-deriving neurons, the retinal ganglion cells (RGCs), may lead to the breakdown of the optical signal transmission from the eye to the brain, thus resulting in a partial or complete vision loss. The causes of optic neuropathy include trauma, ischemia, inflammation, compression, infiltration, and mitochondrial damages. ON injuries include primary and secondary injuries. During these injury phases, various factors orchestrate injured axons to die back and become unable to regenerate, and these factors could be divided into two categories: extrinsic and intrinsic. Extrinsic inhibitory factors refer to the environmental conditions that influence the regeneration of injured axons. The presence of myelin inhibitors and glial scar, lack of neurotrophic factors, and inflammation mediated by injury are regarded as these extrinsic factors. Extrinsic factors need to trigger the intracellular signals to exert inhibitory effect. Proper regulation of these intracellular signals has been shown to be beneficial to ON regeneration. Intrinsic factors of RGCs are the pivotal reasons that inhibit ON regeneration and are closely linked with extrinsic factors. Intracellular cyclic adenosine monophosphate (cAMP) and calcium levels affect axon guidance and growth cone response to guidance molecules. Many genes, such as Bcl-2, PTEN, and mTOR, are crucial in cell proliferation, axon guidance, and growth during development, and play important roles in the regeneration and extension of RGC axons. With transgenic mice and related gene regulations, robust regeneration of RGC axons has been observed after ON injury in laboratories. Although various means of experimental treatments such as cell transplantation and gene therapy have achieved significant progress in neuronal survival, axonal regeneration, and restoration of the visual function after ON injury, many unresolved scientific problems still exist for their clinical applications. Therefore, we still need to overcome hurdles before developing effective therapy to treat optic neuropathy diseases in patients.

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Cytokine-induced SOCS expression is inhibited by cAMP analogue: Impact on regeneration in injured retina

Cited by 83 publications

References 84 publications

Neuroprotective and Axon Growth-Promoting Effects following Inflammatory Stimulation on Mature Retinal Ganglion Cells in Mice Depend on Ciliary Neurotrophic Factor and Leukemia Inhibitory Factor

Neuroprotective and Axon Growth-Promoting Effects following Inflammatory Stimulation on Mature Retinal Ganglion Cells in Mice Depend on Ciliary Neurotrophic Factor and Leukemia Inhibitory Factor

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

Restoration of optic neuropathy

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