Inducible Lentivirus‐Mediated siRNA against TLR4 Reduces Nociception in a Rat Model of Bone Cancer Pain

Pan, Ruirui; Di, Hui-ting; Zhang, Jinming; Huang, Zhengyi; Sun, Yuming; Yu, Weifeng; Wu, Feixiang

doi:10.1155/2015/523896

Cited by 18 publications

(16 citation statements)

References 35 publications

(42 reference statements)

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“…Thus, TLR4 could exert a regulatory function in processing painful stimuli in this model of diet-induced visceral hypersensitivity. Our data are consistent with others studies showing central [ 35 – 39 , 52 ] and peripheral [ 53 , 54 ] alterations of TLR4 associated with several pathological pain states such as inflammatory, neuropathic and cancer pain. As TLR4 is primarily expressed within the CNS in microglial cells [ 15 ], further DIO mice showed enhanced CD11b expression in the PFC and the hippocampus, thus our results are in line with several studies supporting microglia activation as an important factor in the etiology of visceral pain [ 42 , 55 , 56 ].…”

Section: Discussionsupporting

confidence: 93%

“…Protein levels of TLR4 were increased in DIO mice in the prefrontal cortex (t = 6.02; p<0.001, Fig 3A ) and the hippocampus (t = 2.85; p<0.05, Fig 3B ) when compared with lean mice. Other pathological pain states as inflammatory neuropathic and cancer pain have been associated with alterations of TLR4 at the spinal cord level [ 35 – 39 ]. However, spinal TLR4 expression has not been studied in a model of obesity-induced visceral hypersensitivity.…”

Section: Resultsmentioning

confidence: 99%

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Obesity Takes Its Toll on Visceral Pain: High-Fat Diet Induces Toll-Like Receptor 4-Dependent Visceral Hypersensitivity

et al. 2016

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Exposure to high-fat diet induces both, peripheral and central alterations in TLR4 expression. Moreover, functional TLR4 is required for the development of high-fat diet-induced obesity. Recently, central alterations in TLR4 expression have been associated with the modulation of visceral pain. However, it remains unknown whether there is a functional interaction between the role of TLR4 in diet-induced obesity and in visceral pain. In the present study we investigated the impact of long-term exposure to high-fat diet on visceral pain perception and on the levels of TLR4 and Cd11b (a microglial cell marker) protein expression in the prefrontal cortex (PFC) and hippocampus. Peripheral alterations in TLR4 were assessed following the stimulation of spleenocytes with the TLR4-agonist LPS. Finally, we evaluated the effect of blocking TLR4 on visceral nociception, by administering TAK-242, a selective TLR4-antagonist. Our results demonstrated that exposure to high-fat diet induced visceral hypersensitivity. In parallel, enhanced TLR4 expression and microglia activation were found in brain areas related to visceral pain, the PFC and the hippocampus. Likewise, peripheral TLR4 activity was increased following long-term exposure to high-fat diet, resulting in an increased level of pro-inflammatory cytokines. Finally, TLR4 blockage counteracted the hyperalgesic phenotype present in mice fed on high-fat diet. Our data reveal a role for TLR4 in visceral pain modulation in a model of diet-induced obesity, and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity present in pathologies associated to fat diet consumption.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Obesity Takes Its Toll on Visceral Pain: High-Fat Diet Induces Toll-Like Receptor 4-Dependent Visceral Hypersensitivity

et al. 2016

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“…To examine the effects of Peli1 on the induction of neuropathic pain, mice were given 10 μl Peli1 shRNA (2 × 10 8 TU) or 10 μl scrambled shRNA (1 × 10 9 TU) 3 days prior to the beginning of CCI by intrathecal injection. The dosages of shRNA were selected based on previous reports [26,27]. Thermal hyperalgesia and mechanical allodynia were measured before and 3, 5, 7, 11, 14 days after CCI.…”

Section: Experimental Designmentioning

confidence: 99%

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

Wang

Chen

Liu

et al. 2020

J Neuroinflammation

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Background: Spinal cord microglia plays a crucial role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely determined. Here, we investigated the role of Pellino1 (Peli1) and its interplay with spinal microglial activation in neuropathic pain. Methods: In this study, we examined the effects of Peli1 on pain hypersensitivity and spinal microglial activation after chronic constriction injury (CCI) of the sciatic nerve in mice. The molecular mechanisms involved in Peli1mediated hyperalgesia were determined by western blot, immunofluorescence, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). We utilized immunoprecipitation to examine the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) following CCI. In addition, we explored the effect of Peli1 on BV2 microglial cells in response to lipopolysaccharide (LPS) challenge. Results: We found that CCI induced a significant increase in the levels of Peli1, which was present in the great majority of microglia in the spinal dorsal horn. Our results showed that spinal Peli1 contributed to the induction and maintenance of CCI-induced neuropathic pain. The biochemical data revealed that CCI-induced Peli1 in the spinal cord significantly increased mitogen-activated protein kinase (MAPK) phosphorylation, activated nuclear factor kappa B (NF-κB), and enhanced the production of proinflammatory cytokines, accompanied by spinal microglial activation. Peli1 additionally was able to promote K63-linked ubiquitination of TRAF6 in the ipsilateral spinal cord following CCI. Furthermore, we demonstrated that Peli1 in microglial cells significantly enhanced inflammatory reactions after LPS treatment. Conclusion: These results suggest that the upregulation of spinal Peli1 is essential for the pathogenesis of neuropathic pain via Peli1-dependent mobilization of spinal cord microglia, activation of MAPK/NF-κB signaling, and production of proinflammatory cytokines. Modulation of Peli1 may serve as a potential approach for the treatment of neuropathic pain.

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“…TLR4 plays a role in the development of OSAS, as increased expressions of TLR4 could be detected in monocytes extracted from patients with OSAS (Deng et al, ). To blind the target genes, RNA interference (RNAi) is an accurate and powerful gene‐silencing technique by small interfering RNAs (siRNAs), or short hairpin RNAs (shRNAs) (Lan et al, ; Pan et al, ). Few thorough investigations has been reported on blockers specific to TLR4 , and studies on regulating TLR4 expressions by siRNA method may bring new prospects (Wu et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Targeting TLR4 through NF-κB signaling pathway could be stimulated by lipopolysaccharide (LPS) (Lan et al, 2010;Pan et al, 2015). Few thorough investigations has been reported on blockers specific to TLR4, and studies on regulating TLR4 expressions by siRNA method may bring new prospects (Wu et al, 2012).…”

mentioning

confidence: 99%

Effects of small interfering RNA targeting TLR4 on expressions of adipocytokines in obstructive sleep apnea hyponea syndrome with hypertension in a rat model

Nan

Zeng

et al. 2018

Journal Cellular Physiology

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We explored the effects of RNA interference-mediated silencing of TLR4 gene on expressions of adipocytokines in obstructive sleep apnea hyponea syndrome (OSAS) with hypertension in a rat model. Systolic blood pressure of caudal artery and physiological changes were observed when establishing rat models of OSAS with hypertension. Mature rat adipocytes were induced from separated and cultured primary rat adipocytes. To transfect rat mature adipocytes, TLR4 siRNA group and negative control (NC) siRNA group were established. Expressions of TLR4 mRNA of adipocytes were examined after silenced by siRNA by quantitative real-time polymerase chain reaction (qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), expressions of inflammatory cytokines, and adipocytokines of adipocytes were detected. Blood pressure in rat caudal artery was higher in the intermittent hypoxia group than that of the blank control group by 29.87 mmHg, and cardiocytes in the former group showed physiological changes, which indicated successful establishment of rat models of OSAS with hypertension. Red particles could be seen in mature rat adipocytes when stained with Oil Red O. Transfection of TLR4 mRNA was significantly suppressed in the TLR4 siRNA group, which didn't happen in the untransfected control group. Rats in the TLR4 siRNA group had significantly reduced expressions of such inflammatory cytokines as interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) and such adipocytokines as visfatin, adiponectin (ADN), and leptin than those in the untransfected control group. RNA interference-mediated silencing of TLR4 gene could regulate occurrence and development of OSAS with hypertension in rats by downregulating expressions of adipocytokines.

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Inducible Lentivirus‐Mediated siRNA against TLR4 Reduces Nociception in a Rat Model of Bone Cancer Pain

Cited by 18 publications

References 35 publications

Obesity Takes Its Toll on Visceral Pain: High-Fat Diet Induces Toll-Like Receptor 4-Dependent Visceral Hypersensitivity

Obesity Takes Its Toll on Visceral Pain: High-Fat Diet Induces Toll-Like Receptor 4-Dependent Visceral Hypersensitivity

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

Effects of small interfering RNA targeting TLR4 on expressions of adipocytokines in obstructive sleep apnea hyponea syndrome with hypertension in a rat model

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