TLR4/NF-κB signaling activation in plantar tissue and dorsal root ganglion involves in the development of postoperative pain

Xing, Fei; Zhang, Wei; Wen, Jing; Bai, Liying; Gu, Hanwen; Li, Zhisong; Zhang, Jian; Tao, Yuan‐Xiang; Xu, Ji Tian

doi:10.1177/1744806918807050

Cited by 38 publications

(30 citation statements)

References 52 publications

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“…Previous studies have also reported that the inhibition of the NF-κB signaling pathway can protect against IVD degeneration (40,41). It is well known that the TLR4/NF-κB signaling pathway mediates inflammation cascades to amplify the inflammatory response (42,43). In this study, the levels of TNF-α, IL-1β and IL-6 were markedly lower in the LPS + inhibitor group than that in the LPS-stimulated NP cells, while miR-222 mimics enhanced the production of TNF-α, IL-1β and IL-6, in comparison to the LPS group.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of miR-222 inhibits inflammation and the apoptosis of LPS-stimulated human intervertebral disc nucleus pulposus cells

Yang

Zhou

et al. 2019

Int J Mol Med

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It has been demonstrated that miR-222 is upregulated in human intervertebral disc (IVD) degeneration tissues; however, the underlying mechanisms remain unclear. In this study, we aimed to elucidate the mechanisms of action of miR-222 in IVD tissues. Nucleus pulposus (NP) cells were treated with lipopolysaccharide (LPS) to simulate IVD degeneration. The expression level of miR-222 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in cells and tissues. Cell apoptosis was analyzed by flow cytometry. Additionally, western blot analysis was used to determine the levels of Toll-like receptor 4 (TLR4), Iκβ-alpha (IκBα) and p65. Interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and IL-6 protein expression levels were determined by enzyme-linked immunosorbent assay (ELISA). The target gene of miR-222 was determined by TargetScan7.2 and dual luciferase reporter gene analysis. Western blot analysis and RT-qPCR were used to determine the mRNA and protein levels of tissue inhibitor of metalloproteinase 3 (TIMP3). The mRNA expression level of miR-222 was found to be increased in IVD tissues and in LPS-stimulated cells, and its expression was positively associated with the clinical MRI grade. In vitro , apoptosis was promoted/inhibited by miR-222 mimics/inhibitors. Transfection with miR-222 mimics/inhibitors significantly increased/decreased the production of TNF-α, IL-1β and IL-6 and suppressed/enhanced collagen II and aggrecan expression. The protein levels of TLR4, p-IκBα and p-p65 were upregulated/downregulated by transfection with the mimics/inhibitors. In addition, it was demonstrated that TIMP3 was a direct target gene of miR-222, and was negatively regulated by miR-222 in NP cells. The silencing of TIMP3 reversed the inhibitory effects of miR-222 inhibitor on cell apoptosis, which was induced by LPS. Thus, on the whole, the findings of this study demonstrate that miR-222 functions as a promoter of IVD development, partly via the regulation of TIMP3.

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Section: Discussionmentioning

confidence: 99%

Knockdown of miR-222 inhibits inflammation and the apoptosis of LPS-stimulated human intervertebral disc nucleus pulposus cells

Yang

Zhou

et al. 2019

Int J Mol Med

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“…Some animals underwent stereotaxic implantation of an ipsilateral hippocampal depth or surface electrode 25 days or 85 days after FPI or sham injury. Drug dosing was based on published studies in vivo …”

Section: Methodsmentioning

confidence: 99%

“…Drug dosing was based on published studies in vivo. [20][21][22][23] Electrophysiology Six to 8 days after FPI or sham injury, rats were anesthetized with isoflurane and decapitated. Horizontal brain slices (400μm for field recordings and 350μm for whole cell recordings) were prepared as described previously.…”

Section: Drug Administration and Electrode Implantationmentioning

confidence: 99%

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Korgaonkar

Liu

Sekhar

et al. 2020

Annals of Neurology

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Objective Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll‐like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury. Methods Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury. Results The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (CP‐AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. Interpretation These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post‐traumatic neuronal excitability. Moreover, the TLR4‐dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4‐mediated increase in CP‐AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497–515

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“…Other groups further demonstrated that inhibition of IL-1β signaling through antagonism of its receptor significantly decreased postoperative pain-like behavior in rodents (32, 98, 100). Furthermore, additional research has established that inhibition of the upstream mediators of IL-1β, such as TLR4 (98, 103), NF-κB (103), caspase-1 (104), or NLRP3 (13), decreases postoperative pain-like behaviors in rodents. General blockade of IL-1β signaling, like that obtained with FDA approved Anakinra (IL-1R1 antagonist), increases the rate of infections due to the necessity of IL-1β for bacterial infection clearance (105, 106).…”

Section: Proinflammatory Il-1β and Postoperative Painmentioning

confidence: 99%

A Novel Sex-Dependent Target for the Treatment of Postoperative Pain: The NLRP3 Inflammasome

2019

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In recent years the innate immune system has been shown to be crucial for the pathogenesis of postoperative pain. The mediators released by innate immune cells drive the sensitization of sensory neurons following injury by directly acting on peripheral nerve terminals at the injury site. The predominate sensitization signaling pathway involves the proinflammatory cytokine interleukin-1β (IL-1β). IL-1β is known to cause pain by directly acting on sensory neurons. Evidence demonstrates that blockade of IL-1β signaling decreases postoperative pain, however complete blockade of IL-1β signaling increases the risk of infection and decreases effective wound healing. IL-1β requires activation by an inflammasome; inflammasomes are cytosolic receptors of the innate immune system. NOD-like receptor protein 3 (NLRP3) is the predominant inflammasome activated by endogenous molecules that are released by tissue injury such as that which occurs during neuropathic and inflammatory pain disorders. Given that selective inhibition of NLRP3 alleviates postoperative mechanical pain, its selective targeting may be a novel and effective strategy for the treatment of pain that would avoid complications of global IL-1β inhibition. Moreover, NLRP3 is activated in pain in a sex-dependent and cell type-dependent manner. Sex differences in the innate immune system have been shown to drive pain and sensitization through different mechanisms in inflammatory and neuropathic pain disorders, indicating that it is imperative that both sexes are studied when researchers investigate and identify new targets for pain therapeutics. This review will highlight the roles of the innate immune response, the NLRP3 inflammasome, and sex differences in neuropathic and inflammatory pain.

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TLR4/NF-κB signaling activation in plantar tissue and dorsal root ganglion involves in the development of postoperative pain

Cited by 38 publications

References 52 publications

Knockdown of miR-222 inhibits inflammation and the apoptosis of LPS-stimulated human intervertebral disc nucleus pulposus cells

Knockdown of miR-222 inhibits inflammation and the apoptosis of LPS-stimulated human intervertebral disc nucleus pulposus cells

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

A Novel Sex-Dependent Target for the Treatment of Postoperative Pain: The NLRP3 Inflammasome

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