Effect of adenovirus-mediated RNA interference of IL-1β expression on spinal cord injury in rats

Wp, Lin; Jh, Lin; Cai, Baochang; Jx, Shi; Wj, Li; Gr, Choudhury; Sq, Wu; Jz, Wu; Hp, Wu; Qf, Ke

doi:10.1038/sc.2016.20

Cited by 20 publications

(17 citation statements)

References 36 publications

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“…7). [47][48][49][50] MMP-12 production was reduced by 50%. This protein is increased by more than 180-fold in spinal cord injury and has been linked to blood-brain barrier disruption, infiltration of immune cells, and worse outcome.…”

Section: Discussionmentioning

confidence: 94%

RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response

Kwan

Floyd

Kim

et al. 2017

Journal of Neurotrauma

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Inflammation plays a prominent role in the events following traumatic injury to the central nervous system (CNS). The initial inflammatory response is driven by mediators such as tumor necrosis factor α and interleukin 1β, which are produced by activated astrocytes and microglia at the site of injury. These factors are regulated post-transcriptionally by RNA binding proteins (RBP) that interact with adenylate and uridylate-rich elements (ARE) in the 3'-untranslated region of the messenger RNA (mRNA). Human antigen R (HuR) is one of these RBPs and generally functions as a positive regulator of ARE-containing mRNAs. Here, we hypothesized that HuR plays an important role in the induction of cytokine and chemokines in astrocytes following traumatic injury. Using a mouse model of spinal cord injury, we found HuR to be extensively translocated to the cytoplasm in astrocytes at the level of injury, consistent with its activation. In an in vitro stretch injury model of CNS trauma, we observed a similar cytoplasmic shift of HuR in astrocytes and an attenuation of cytokine induction with HuR knockdown. RNA kinetics and luciferase assays suggested that the effect was more related to transcription than RNA destabilization. A small molecule inhibitor of HuR suppressed cytokine induction of injured astrocytes and reduced chemoattraction for neutrophils and microglia. In summary, HuR is activated in astrocytes in the early stages of CNS trauma and positively regulates the molecular response of key inflammatory mediators in astrocytes. Our findings suggest that HuR may be a therapeutic target in acute CNS trauma for blunting secondary tissue injury triggered by the inflammatory response.

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Section: Discussionmentioning

confidence: 94%

RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response

Kwan

Floyd

Kim

et al. 2017

Journal of Neurotrauma

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“…Moreover, IL-1β can inhibit the functional recovery after neural stem cell transplant administered to treat SCI in rats [34], and may downgrade the prognosis of SCI [35]. Importantly, downregulation of IL-1β after traumatic SCI may be potentially protective, for reducing secondary impairments and improving the outcomes [36]. Furthermore, IL-18 levels correlated with the severity of SCI [37].…”

Section: Discussionmentioning

confidence: 99%

Dopamine Reduced Pyroptosis and Improved Functional Recovery After Spinal Cord Injury 

Zhu

Ding

et al. 2020

Preprint

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Background: Neuronal loss, demyelination, and an excessive inflammatory response accompany the pathogenesis of spinal cord injury (SCI). The inflammatory response is promoted by inflammasomes in variety diseases. Dopamine is a neurotransmitter that also functions as a regulator in NLRP3 (nucleotide-binding oligomerization domain-like receptor 3) inflammasome-dependent neuroinflammation. However, the effects and molecular mechanisms underlying the role of dopamine in SCI are little known. Methods:Functional recovery was assessed using Basso Mouse Scale (BMS) and BMS subscore. Histopathologic damage was evaluated by H&E staining. Demyelination was evaluated using immunofluorescence staining of myelin basic protein. Neuronal loss was evaluated by immunochemistry staining of NeuN. Pyroptosis was assessed by flow cytometry, western blot, and cell viability and cytotoxicity assays.Results: This study using mice showed that dopamine was significantly associated with enhanced locomotor recovery after SCI; with a reduction in NLRP3 inflammasome activation, pyroptosis, neuron and myelin loss, and histological changes. In vitro data suggested an association between dopamine and suppressed NLRP3 inflammasome activation and neuronal pyroptosis, and greater survival of neurons. Conclusion: Thus, dopamine may be a novel and effective approach for improving recovery after SCI.

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“…IL-1β contributes strongly to detrimental effects on lesion development(in terms of glia activation and size) and the plasticity of axons after SCI [38].Furthermore, IL-1β may be implicated in the prognosis of SCI [39].IL-1β is reported to dampen functional recovery after neural stem cell transplant therapy in SCI rats [40]. Importantly, reduction of IL-1β expression have been shown to be exhibit potential bene cial effects for mitigation of tissue damage and ameliorating the outcomes [41]. In addition, IL-18 is closely related with the severity of SCI [42].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Caspase-1 by VX-765 Reduces Pyroptosis and Attenuates Neuroinflammation After Spinal Cord Injury

Zhu

Ding

et al. 2020

Preprint

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Background: Excessive inflammatory response, neuronal loss, and demyelination mediate the pathogenesis of spinal cord injury (SCI). VX-765, a highly selective caspase-1 inhibitor, is recently revealed to control pyroptosis in some disease models. However, the effects and underlying mechanisms of VX-765 in SCI remains unclear. Methods: Functional recovery was assessed using Basso Mouse Scale (BMS) and BMS subscore. Proinflammatory cytokines levels was evaluated by western blot or enzyme-linked immunosorbent assay. The number of neutrophils was assessed by flow cytometry. Neuronal loss was evaluated by immunochemistry staining of NeuN. Demyelination was evaluated using immunofluorescence staining of myelin basic protein. Results: Here we report that VX-765 led to a significant recovery of hindlimb locomotor function after SCI in mice. Moreover, VX-765 prevented caspase-1 activation, inhibited pyroptosis of neuron and oligodendrocyte, reduced proinflammatory cytokines levels and loss of neuron and myelin, and declines the number of neutrophils in mice. Furthermore, VX-765 suppressed caspase-1 activation, decreased proinflammatory cytokine levels, diminished pyroptosis and promoted the survival of neurons in oxygen-glucose deprivation oligodendrocytes.Conclusions: Together, our data indicate that VX-765 provide a novel potential therapy strategy to improve recovery after SCI.

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Effect of adenovirus-mediated RNA interference of IL-1β expression on spinal cord injury in rats

Abstract: This study demonstrated that the IL-1β downregulation may have potential therapeutic benefits for both reducing secondary damages and improving the outcomes after traumatic SCI.

Cited by 20 publications

References 36 publications

RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response

RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response

Dopamine Reduced Pyroptosis and Improved Functional Recovery After Spinal Cord Injury

Inhibition of Caspase-1 by VX-765 Reduces Pyroptosis and Attenuates Neuroinflammation After Spinal Cord Injury

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Effect of adenovirus-mediated RNA interference of IL-1β expression on spinal cord injury in rats

Abstract: This study demonstrated that the IL-1β downregulation may have potential therapeutic benefits for both reducing secondary damages and improving the outcomes after traumatic SCI.

Cited by 20 publications

References 36 publications

RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response

RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response

Dopamine Reduced Pyroptosis and Improved Functional Recovery After Spinal Cord Injury&nbsp;

Inhibition of Caspase-1 by VX-765 Reduces Pyroptosis and Attenuates Neuroinflammation After Spinal Cord Injury

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Dopamine Reduced Pyroptosis and Improved Functional Recovery After Spinal Cord Injury