TNF-α/STAT3 pathway epigenetically upregulates Nav1.6 expression in DRG and contributes to neuropathic pain induced by L5-VRT

Ding, Huan‐Huan; Zhang, Subo; Lv, Yan; Ma, Chao; Li, Meng; Zhang, Kuibo; Ruan, Xiuxiu; Wei, Jia-You; Xin, Wenjun; Wu, Shaoling

doi:10.1186/s12974-019-1421-8

Cited by 53 publications

(55 citation statements)

References 29 publications

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“…Apparently, the double-labeled immunofluorescence results were not in line with the prevailing view but were still consistent with some other former studies. 55,56 Similarly, the enhanced IL-1b expression was detected on the neurons of BCP rats, aggravating inflammation of spinal dorsal horn. We must admit that a large number of studies showed that astroglia or microglia secreted IL-1b activated neurons through IL-1R during inflammation or neuropathic pain.…”

Section: Discussionmentioning

confidence: 95%

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

et al. 2019

Mol Pain

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Curcumin has several pharmacological properties such as anti-inflammatory, antioxidant, and neuroprotective activities. B14 is a curcumin analogue and is considered to be a more potent compound with preserved pharmacodynamic activities. Based on the previous research studies, janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a remarkable role in inflammation, chronic pain, and even contributes to the pathogenesis of neuropathic pain. Pro-inflammatory cytokines interleukin-1b is a downstream factor of JAK2/STAT3 signal transition pathway, which participates in neuron injury and inflammation. We hypothesized that this signal transition pathway played an indispensable role in bone cancer pain. We herein established a bone cancer pain model to monitor the variation of JAK2/STAT3 signal transduction pathway and measured the effect of B14. The results in bone cancer pain model showed that (i) the levels of interleukin-1b were elevated, and the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 were increased; (ii) double immunostaining showed that p-JAK2, p-STAT3, and interleukin-1b were colocalized primarily with neurons, rather than with astrocytes or microglial cells; (iii) B14 injection (intraperitoneally) markedly eased bone cancer pain; (iv) Western blotting showed that B14 injection lowered p-JAK2, p-STAT3, and interleukin-1b levels, meanwhile the ratios of p-JAK2/ JAK2 and p-STAT3/STAT3 was reduced; (v) immunofluorescence results also confirmed decreased levels of p-JAK2, p-STAT3, and interleukin-1b in B14 treatment group. These findings suggested that B14 injection attenuated bone cancer pain in rats. This intervention inhibited JAK2/STAT3 cascade activation, downregulating interleukin-1b expression in spinal dorsal horn.

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Section: Discussionmentioning

confidence: 95%

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

et al. 2019

Mol Pain

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“…Moreover, an altered DNA methylation pattern has been demonstrated in neurodegenerative diseases, such as AD and PD [ 26 ], which are typically characterized by neuroinflammation and a predominant presence of TNFα cytokine. Interestingly, DNA methylation changes and other epigenetic mechanisms underlying TNFα-mediated effects have been reported in a number of cell types [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Overall, these findings suggest the importance of analyzing epigenetic actions of TNFα in human neuronal models.…”

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

Guarnieri

Sarchielli

Comeglio

et al. 2020

IJMS

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TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.

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“…Similarly, activated p38 can also directly regulate the phosphorylation of the Nav1.8 channel and increase the level of TRPV1 in the DRG neurons [61,63]. Furthermore, proinflammatory cytokines upregulate the expression of Nav1.7 and Nav1.6, which contributes to peripheral sensitization and neuropathic pain [64,65]. Therefore, the activation of TLR8 may increase the neuronal excitability of TG neurons via regulating the expression and function of sodium channel.…”

Section: Tlr8 Is Involved In the Increase Of Intracellular Calcium Anmentioning

confidence: 99%

TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain

Zhao

Bai

Cao

et al. 2020

Preprint

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Background: Trigeminal neuropathic pain (TNP) is a significant health problem whereas the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) are recently demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. How TLR8 is expressed in the trigeminal ganglion (TG) after infraorbital nerve injury and whether TLR8 is involved in TNP have not been investigated. Methods: TNP model was established by the partial infraorbital nerve ligation (pIONL) in mice. The effect of TLR8 and its agonist VTX-2337 on pain hypersensitivity was checked by facial pain behavioral test. The immunostaining, real-time RT-PCR, and western blot were used to evaluate the expression of TLR8, pERK, pp38, and proinflammatory cytokines in the TG. The intracellular concentration of Ca 2+ was detected by the calcium imaging.Results: TLR8 was persistently increased in TG neurons in pIONL-induced TNP model. In addition, deletion of Tlr8 or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38, and decreased the expression of proinflammatory cytokines in the TG. Furthermore, intra-TG injection of TLR8 agonist VTX-2337 induced facial pain hypersensitivity. VTX-2337 also increased intracellular calcium concentration, induced activation of ERK and p38, and increased the proinflammatory cytokines expression in the TG.Conclusions: TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP. BackgroundThe sensation of nociceptive stimuli is mediated by primary sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG), which transmit noxious information to brain via spinal cord and medulla oblongata, respectively. The painful sensation of orofacial area is relayed in the TG, which gives three major branches: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). Trigeminal neuropathic pain (TNP) is usually a result of injury or disease of one or more nerve branches (usually V2 and/or V3) of the TG and can be triggered by subtle sensory stimuli to the affected side of the face, such as light mechanical touch, brushing teeth, and chewing 4 [1]. TNP is a chronic state and difficult to treat in clinical practice. Understanding the pathophysiology of TNP is essential for the management of the pain.In recent years, increasing evidence revealed that neuroinflammation is involved in the pathological process of neuropathic pain including TNP [2, 3]. After peripheral nerve injury, neuroinflammation occurs at different anatomical locations on the pain transmission pathway, including TG/DRG and medulla oblongata/spinal cord, which facilitates peripheral sensitization and central sensitization [4][5][6]. Among the inflammatory mediators, the cytokines such as TNF-α, IL-1β, and IL-6 are well demonstrated to be increased in the peripheral nervous system after nerve injury and enhance neuronal excitability...

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TNF-α/STAT3 pathway epigenetically upregulates Nav1.6 expression in DRG and contributes to neuropathic pain induced by L5-VRT

Cited by 53 publications

References 29 publications

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain

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