Etanercept decreases HMGB1 expression in dorsal root ganglion neuron cells in a rat chronic constriction injury model

Abstract

In the present study, we examined the effect of etanercept on high mobility group box 1 (HMGB1) expression in dorsal root ganglion (DRG) neuron cells in a rat model of chronic constriction injury (CCI) of the sciatic nerve, with the aim of exploring the molecular mechanism underlying the therapeutic effect of etanercept on sciatica-related nociception and the potential interaction between tumor necrosis factor-α (TNF-α) and HMGB1 in DRG neuron cells. A rat CCI model was employed and the animals were randomly assigned to seven groups (n=20/group): untreated, sham only, sham/saline, sham/etanercept, CCI only, CCI/saline and CCI/etanercept. Our results revealed that compared with the sham/saline and sham/etanercept groups, thermal hyperalgesia and mechanical hyperalgesia, as well as HMGB1 expression at both the mRNA and protein levels in the DRG neuron cells, were induced by CCI, and were significantly inhibited by etanercept. Although etanercept showed no significant effect on the sham group, it significantly reduced the phosphorylated p38 mitogen-activated protein kinase (MAPK) levels induced by CCI in the DRG neuron cells. In conclusion, we demonstrated that etanercept significantly decreased the HMGB1 expression induced by CCI in the DRG neuron cells. This study not only explored the molecular mechanisms underlying the therapeutic effect of etanercept on sciatica-related nociception, but also provided indirect evidence for an interaction between TNF-α and HMGB1 in DRG neuron cells.

Cannabinoid WIN-55,212-2 mesylate inhibits tumor necrosis factor-α-induced expression of nitric oxide synthase in dorsal root ganglion neurons

“…Jia et al showed that TNF-α could phosphorylate and activate p38 MAPK ( 22 ). Wang et al showed that a specific TNF-α inhibitor significantly reduced phosphorylated p38 MAPK levels induced by chronic constriction injury in DRG neurons ( 23 ). Xu et al suggested that p38 MAPK activation in DRG neurons is necessary for the initiation and maintenance of neuropathic pain ( 24 ).…”

Neuropathic Pain in Rats with a Partial Sciatic Nerve Ligation Is Alleviated by Intravenous Injection of Monoclonal Antibody to High Mobility Group Box-1

“…Several studies have demonstrated that TNF-α is secreted from cultured microglia and DRG neurons, and that TNF-α stimulation modulates the expression and secretion of HMGB1 [27], [32], [35]. Furthermore, Wang et al reported that the intrathecal injection of Etanercept, a recombinant TNF receptor (p75)-Fc fusion protein, inhibited the increased expression of HMGB1 by chronic constriction injury of the sciatic nerve [36]. In addition, HMGB1 release occurs considerably later than the secretion of typical pro-inflammatory mediators TNF-α and interleukin (IL)-1 [3], [34].…”

Role of high‐mobility group box 1 and its modulation by thrombomodulin/thrombin axis in neuropathic and inflammatory pain

“…HMGB1 has three cysteine residues (C23, C45 and C106), and all-thiol (at) or fully reduced HMGB1 can be oxidized into disulfide (ds)-HMGB1 with a disulfide bond between C23 and C45 in box A (Figure 1a). There is plenty of evidence that at-HMGB1 and ds-HMGB1 in the extracellular environment activate separate membrane receptors, for example, advanced glycation end-product specific receptor (receptor for advanced glycation end-products; RAGE) and TLR4 respectively (Kang et al, 2014;Wan et al, 2016;Xu et al, 2019;Figure 1b). Sulfonyl HMGB1, in which all three cysteines are oxidized to sulfonates, has no activity in cell migration or cytokine induction, and its biological function is unknown (Kang et al, 2014;Venereau et al, 2012).…”

“…Accumulating evidence has demonstrated that peripheral and central HMGB1 plays a role in processing of somatic and visceral nociception and participates in the pathogenesis of inflammatory and neuropathic pain (Kang et al, 2014;J. Kato & Svensson, 2015;Kawabata, Tsubota, Sekiguchi, & Tsujita, 2019;Tsubota et al, 2019;Wan et al, 2016). In the brain, extracellular HMGB1 derived from neurons or glial cells also appears to be involved in a variety of neuroinflammatory and neurodegenerative diseases, such as stroke, epilepsy (Nishibori, Mori, & Takahashi, 2019), alcoholism (Crews, Lawrimore, Walter, & Coleman, 2017), Alzheimer's disease (Okazawa, 2017;Venegas & Heneka, 2017), Parkinson's disease (Angelopoulou, Piperi, & Papavassiliou, 2018) and depression (H. Zhang, Ding, Shen, & Peng, 2019).…”

“…Several studies using a rat model of neuropathic pain induced by chronic constriction injury of the sciatic nerve (CCI) show the increased expression of HMGB1 and TLR4 or RAGE in the spinal cord or DRG neurons after CCI and indicate that suppression of HMGB1 expression by i.t. administration of shRNA or microRNAs targeting HMGB1 reduces the CCI‐induced neuropathic pain (He et al, 2013; Kuang et al, 2012; Tian et al, 2020; R. K. Wang et al, 2013; Xia et al, 2018; J. Zhang, Zhang, & Zi, 2015). There is also a report showing the role of HMGB1 in a model for sciatic pain caused by application of autologous nucleus pulposus to the DRG (Otoshi et al, 2011).…”