Double‐stranded RNA induces iNOS gene expression in Schwann cells, sensory neuronal death, and peripheral nerve demyelination

Lee, Hyunkyoung; Park, Chanhee; Cho, Ik‐Hyun; Kim, Hyun Yeong; Jo, Eun-Kyeong; Lee, Soojin; Kho, Hong‐Seop; Choi, Se‐Young; Oh, Seunghee; Park, Kyungpyo; Kim, Joong Soo; Lee, Sung Joong

doi:10.1002/glia.20493

Cited by 29 publications

(26 citation statements)

References 40 publications

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“…Interestingly, iNOS induction by viral RNA in this model depends on toll-like receptor 3 and requires activation of JNKs (Lee et al, 2007), suggesting a link between the c-Jun pathway and NO signaling in Schwann cell demyelination.…”

Section: Nitric Oxide Synthasementioning

confidence: 72%

“…Following injury to the sciatic nerve, inducible nitric oxide synthase (iNOS) is upregulated in the distal stump although it is not clear to what extent this takes place in Schwann cells rather than macrophages (Gonzalez-Hernandez and Rustioni, 1999;Lee et al, 2007;Levy and Zochodne, 1998;Levy et al, 1999Levy et al, , 2001. In iNOS null mice, uninjured nerves show no obvious abnormalities, but myelin breakdown, judged by morphological criteria, is markedly delayed after transection, nerve crush or chronic constriction injury (Levy et al, 2001).…”

Section: Nitric Oxide Synthasementioning

confidence: 99%

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Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Jessen

Mirsky

2008

Glia

450

409

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Dedifferentiation of myelinating Schwann cells is a key feature of nerve injury and demyelinating neuropathies. We review recent evidence that this dedifferentiation depends on activation of specific intracellular signaling molecules that drive the dedifferentiation program. In particular, we discuss the idea that Schwann cells contain negative transcriptional regulators of myelination that functionally complement positive regulators such as Krox-20, and that myelination is therefore determined by a balance between two opposing transcriptional programs. Negative transcriptional regulators should be expressed prior to myelination, downregulated as myelination starts but reactivated as Schwann cells dedifferentiate following injury. The clearest evidence for a factor that works in this way relates to c-Jun, while other factors may include Notch, Sox-2, Pax-3, Id2, Krox-24, and Egr-3. The role of cell-cell signals such as neuregulin-1 and cytoplasmic signaling pathways such as the extracellular-related kinase (ERK)1/2 pathway in promoting dedifferentiation of myelinating cells is also discussed. We also review evidence that neurotrophin 3 (NT3), purinergic signaling, and nitric oxide synthase are involved in suppressing myelination. The realization that myelination is subject to negative as well as positive controls contributes significantly to the understanding of Schwann cell plasticity. Negative regulators are likely to have a major role during injury, because they promote the transformation of damaged nerves to an environment that fosters neuronal survival and axonal regrowth. In neuropathies, however, activation of these pathways is likely to be harmful because they may be key contributors to demyelination, a situation which would open new routes for clinical intervention. V V C 2008 Wiley-Liss, Inc.

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Section: Nitric Oxide Synthasementioning

confidence: 72%

Section: Nitric Oxide Synthasementioning

confidence: 99%

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Jessen

Mirsky

2008

Glia

450

409

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“…Gene expression levels were normalized to the mouse GAPDH gene and represented as fold induction. The fold induction was calculated using the 2 -ΔΔCT method as previously described [14] . All real-time RT-PCR experiments were performed at least 3 times and mean ± SEM values were presented unless otherwise noted.…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

“…Toluidine blue staining was performed as previously described with minor modifications [14] . At 3 and 7 days after sciatic nervecrush injury (days post injury, dpi), wild-type and TLR3 knock-out mice were perfused with 0.1 M phosphate buffer (PB) (pH 7.4) and fixed with 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 M PB.…”

Section: Toluidine Blue Stainingmentioning

confidence: 99%

Toll-Like Receptor 3 Contributes to Wallerian Degeneration after Peripheral Nerve Injury

Lee

Baek²,

Min³

et al. 2016

Neuroimmunomodulation

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Objective: It is well known that Schwann cells play an important role in Wallerian degeneration after peripheral nerve injury. Previously, we reported that toll-like receptor 3 (TLR3) is expressed on Schwann cells, implicating its role in Schwann cell activation during Wallerian degeneration. In this study, we tested this possibility using TLR3 knock-out mice. Methods: Sciatic nerve-crush injury was induced in wild-type and TLR3 knock-out mice. Histological sections of the sciatic nerve were analyzed for Wallerian degeneration on days 3 and 7 after injury. The level of macrophage infiltration was measured by real-time RT-PCR, flow cytometry and immunohistochemistry. The macrophage-recruiting chemokine gene expressions in the injured nerve were determined by real-time RT-PCR. Results: In TLR3 knock-out mice, the nerve injury-induced axonal degeneration and subsequent axonal debris clearance were reduced compared to in wild-type mice. In addition, nerve injury-induced macrophage infiltration into injury sites was attenuated in TLR3 knock-out mice and was accompanied by reduced expression of macrophage-recruiting chemokines such as CC-chemokine ligands (CCL)2/MCP-1, CCL4/MIP-1β and CCL5/RANTES. These macrophage-recruiting chemokines were induced in primary Schwann cells upon TLR3 stimulation. Finally, intraneural injection of polyinosinic-polycytidylic acid, a synthetic TLR3 agonist, induced macrophage infiltration into the sciatic nerve in vivo. Conclusion: These data show that TLR3 signaling contributes to Wallerian degeneration after peripheral nerve injury by affecting Schwann cell activation and macrophage recruitment to injured nerves.

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“…Neurotrophic factors may also be involved in triggering programmed cell death and demyelination following injury. For example, NT3 inhibits myelination when added exogenously to co-cultures in vitro (Chan et al, 2001), and induction of NO expression by Schwann cells promotes neuron cell death in culture (Lee et al, 2007). Since the hydrostatic compression chamber system does not require media cycling, it has been specifically designed for the study of complex co-cultures that involve paracrine signaling (i.e., myelinated co-cultures), and may be used to further elucidate the role of these signaling factors in the cellular response to mechanical stimuli.…”

mentioning

confidence: 99%

AnIn-VitroTraumatic Model To Evaluate the Response of Myelinated Cultures to Sustained Hydrostatic Compression Injury

Frieboes

Gupta

2009

Journal of Neurotrauma

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While a variety of in-vitro models have been employed to investigate the response of load-bearing tissues to hydrostatic pressure, long-term studies are limited by the need to provide for adequate gas exchange during pressurization. Applying compression in vitro may alter the equilibrium of the system and thereby disrupt the gas exchange kinetics. To address this, several sophisticated compression chamber designs have been developed. However, these systems are limited in the magnitude of pressure that can be applied and may require frequent media changes, thereby eliminating critical autocrine and paracrine signaling factors. To better isolate the cellular response to long-term compression, we created a model that features continuous gas flow through the chamber during pressurization, and a negative feedback control system to rigorously control dissolved oxygen levels. Monitoring dissolved oxygen continuously during pressurization, we find that the ensuing response exhibits characteristics of a second-or higher-order system which can be mathematically modeled using a second-order differential equation. Finally, we use the system to model chronic nerve compression injuries, such as carpal tunnel syndrome and spinal nerve root stenosis, with myelinated neuron-Schwann cell co-cultures. Cell membrane integrity assay results show that co-cultures respond differently to hydrostatic pressure, depending on the magnitude and duration of stimulation. In addition, we find that myelinated Schwann cells proliferate in response to applied hydrostatic compression.

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Double‐stranded RNA induces iNOS gene expression in Schwann cells, sensory neuronal death, and peripheral nerve demyelination

Cited by 29 publications

References 40 publications

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Toll-Like Receptor 3 Contributes to Wallerian Degeneration after Peripheral Nerve Injury

AnIn-VitroTraumatic Model To Evaluate the Response of Myelinated Cultures to Sustained Hydrostatic Compression Injury

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