SOCS3-Mediated Blockade of JAK/STAT3 Signaling Pathway Reveals Its Major Contribution to Spinal Cord Neuroinflammation and Mechanical Allodynia after Peripheral Nerve Injury

Domı́nguez, Elisa; Mauborgne, A.; Mallet, Jacques; Desclaux, Mathieu; Pohl, Michel

doi:10.1523/jneurosci.5007-09.2010

Cited by 173 publications

(146 citation statements)

References 44 publications

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“…78 To what extent these endogenous inhibitory mechanisms are involved in inflammatory pain remains to be elucidated in detail. As has been already pointed out above, interference with IL-6 signaling via SOCS3-overexpression reduced mechanical hyperalgesia after nerve lesion in rats, 42 indicating that the negative regulators may represent promising targets for the treatment of pain. Synthetic JAK inhibitors act at the same level as SOCS proteins and prevent STAT activation.…”

Section: How Does Inhibition Of the Jak-stat Pathwaymentioning

confidence: 60%

“…Additionally, the blockade of JAK-STAT3 activity by lentiviral-mediated production of the suppressor of cytokine signaling (SOCS) 3 prevented the strong expression of IL-6 and of other factors induced in the spinal cord after nerve lesion in rats and substantially attenuated mechanical allodynia. 42 In vitro experiments indicated that TNF-α induces The antinociceptive effect of anti-inflammatory cytokines is largely mediated via JAK/STAT activation resulting in the inhibition of the production and/or release of pro-inflammatory cytokines. Most pro-inflammatory cytokines indirectly contribute to hyperalgesia by enhancing the synthesis or release of prostaglandins, sympathetic amines, endothelin, and NGF.…”

Section: Pronociceptive Cytokinesmentioning

confidence: 99%

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IL-4, JAK-STAT signaling, and pain

Busch-Dienstfertig

González-Rodríguez

2013

JAK-STAT

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Section: How Does Inhibition Of the Jak-stat Pathwaymentioning

confidence: 60%

Section: Pronociceptive Cytokinesmentioning

confidence: 99%

IL-4, JAK-STAT signaling, and pain

Busch-Dienstfertig

González-Rodríguez

2013

JAK-STAT

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“…to neuro-inflammation [69] and promotes neuronal survival and regeneration [70] after SCi, is one of the most important transducers in the process of glial scar formation. A marked reduction of glial scarring and a significant improvement of locomotion occur in animals with conditional knockdown of STAT3 compared with their wild-type counterparts [71] .…”

Section: Signal Transducer and Activator Of Transcription And Interlementioning

confidence: 99%

The glial scar in spinal cord injury and repair

2013

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Glial scarring following severe tissue damage and inflammation after spinal cord injury (SCi) is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCi. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCi.Keywords: glial scar; spinal cord injury; axonal regeneration; astrocyte activation; reactive astrogliosis; neuroinflammation IntroductionSpinal cord injury (SCi) is a common and devastating central nervous system (CNS) insult that results in disruption of cord microstructure and is followed by limited neuronal regeneration and insufficient functional recovery in adult mammals. After severe SCi, and in response to changes in the local microenvironment, astrocytes, the most abundant glial cells in the CNS, transform into reactive astrocytes and undergo dramatic morphological changes [1] as well as massive variations in gene expression [2] . Reactive astrocytes, the major component of glial scars, along with other cells in the spinal cord and blood-borne cells leaking from the damaged blood-spinal cord barrier, participate in the process of scar formation [3] .From the historical perspective, a glial scar is recognized as an impediment to the regeneration of axons in the cord because of the irregular rearrangement of hypertrophic astrocytic processes, as well as major components of the axonal inhibitory extracellular matrix (ECM), including chondroitin sulfate proteoglycans (CSPGs) that are secreted by the reactive astrocytes [4] . Currently, increasing evidence is advancing our knowledge of the mechanism of the formation of glial scars after a lesion and the roles of glial scars in the regulation of neuro-inflammation and repair processes [5,6] .This article reviews the following: (1) the molecular and cellular properties of glial scar formation following SCi;(2) the roles of glial scar formation in axonal regeneration and neuro-inflammation; and (3) the current status of scarmodulating therapeutic strategies for spinal cord repair after injury. Molecular and Cellular Properties of Glial Scars Characterization of Glial ScarsTraumatic damage of the spinal cord can result in seallike scar tissue in the lesion zone, which is filled with dense cellular components and a connective matrix. Generally, the scar tissue is classified into two parts, fibrotic and glial. 422The fibrotic scar, primarily composed of invading fibrobl...

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“…Among these wellstudied pathways, STAT1 plays a critical role in signal transduction as a transcription factor by binding specifically onto surface receptors, resulting in its phosphorylation and nuclear translocation (Calapai et al, 2000;Wang et al, 2006;Dominguez et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Alleviation of spinal cord injury by Ginkgolide B via the inhibition of STAT1 expression

Zheng

Cao

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Ginkgolide B has been known to inhibit cell apoptosis by modulating multiple cytokines and plays an important role in neuroprotection. Signal transducer and activator of transcription 1 (STAT1) has been studied in a spinal cord injury (SCI) model. However, the role of Ginkgolide B in SCI treatment remains unclear. This study investigated the potential mechanism of Ginkgolide B using an SCI rat model. SD rats were used to generate an SCI model followed by Ginkgolide B injection (4 mg/kg) for 14 days. Spinal cord tissue samples were examined using hematoxylin and eosin (H&E) staining. The expression of STAT1 was determined by western blot. Using a dyskinesia scale, intervention with Ginkgolide B significantly decreased the severity of SCI. H&E staining revealed less nuclear condensation and cell necrosis in SCI rats after treatment with Ginkgolide B. STAT1 expression was significantly increased in SCI model rats, but was lower after Ginkgolide B treatment. Therefore, Ginkgolide B can effectively inhibit STAT1 expression and alleviate SCI.

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SOCS3-Mediated Blockade of JAK/STAT3 Signaling Pathway Reveals Its Major Contribution to Spinal Cord Neuroinflammation and Mechanical Allodynia after Peripheral Nerve Injury

Cited by 173 publications

References 44 publications

IL-4, JAK-STAT signaling, and pain

IL-4, JAK-STAT signaling, and pain

The glial scar in spinal cord injury and repair

Alleviation of spinal cord injury by Ginkgolide B via the inhibition of STAT1 expression

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