Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib

Liu, Cuicui; Huang, Zhuxi; Li, Xiao; Shen, Kai-Feng; Li, Meng; Ouyang, Handong; Zhang, Subo; Ruan, Yan; Zhang, Xiaolong; Wu, Shaoling; Xin, Wenjun; Ma, Chao

doi:10.1016/j.expneurol.2018.01.011

Cited by 71 publications

(51 citation statements)

References 44 publications

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“…Consistent evidence suggests increased expression of NLRP3 inflammasome in macrophages infiltrating DRG and sciatic nerves, and this might contribute to the development of neuropathic pain in short-term PTX-treated rats [ 38 ]. It is also remarkable that inhibition of NLRP3-mediated inflammatory response in the spinal cord results in the attenuation of mechanical hypersensitivity in mouse models of neuropathic pain, underscoring the link between pain and inflammation [ 39 ] Similar data have also very recently been reported also following bortezomib administration using an acute (five consecutive days) experimental setting in rats [ 40 ].…”

Section: Discussionmentioning

confidence: 76%

High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats

Meregalli

Marjanović

Scali

et al. 2018

J Neuroinflammation

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BackgroundChemotherapy-induced peripheral neurotoxicity (CIPN) is a severe adverse effect in patients receiving antitumor agents, and no effective treatment is available. Although the mechanisms responsible for the development of CIPN are poorly understood, recent findings make neuroinflammation an attractive target to be investigated, particularly when neuropathic pain is a prominent feature such as after bortezomib administration.The aim of our study was to evaluate the effect of intravenous immunoglobulins (IVIg) delivery in chronic CIPN. The related neuro-immune aspects were investigated in a well-characterized rat model of bortezomib-induced peripheral neurotoxicity (BIPN).MethodsAfter determination of a suitable schedule based on a preliminary pharmacokinetic pilot study, female Wistar rats were treated with IVIg 1 g/kg every 2 weeks. IVIg treatment was started at the beginning of bortezomib administration (“preventive” schedule), or once BIPN was already ensued after 4 weeks of treatment (“therapeutic” schedule). Neurophysiological and behavioral studies were performed to assess the extent of painful peripheral neurotoxicity induced by bortezomib, and these functional assessments were completed by pathologic examination of peripheral nerves and intraepidermal nerve fiber quantification (IENF). The role of the innate immune response in BIPN was investigated by immunochemistry characterization of macrophage infiltration in peripheral nerves.ResultsBoth schedules of IVIg administration were able to significantly reduce bortezomib-induced heat and mechanical allodynia. Although these changes were not evidenced at the neurophysiological examination of peripheral nerves, they behavioral effects were paralleled in the animals treated with the preventive schedule by reduced axonopathy in peripheral nerves and significant protection from loss of IENF. Moreover, IVIg administration was very effective in reducing infiltration in peripheral nerves of macrophages with the M1, pro-inflammatory phenotype.ConclusionOur results suggest a prominent role of neuroinflammation in BIPN and that IVIg might be considered as a possible safe and effective therapeutic option preventing M1 macrophage infiltration. However, since neuropathic pain is frequent also in other CIPN types, it also indicates the need for further investigation in other forms of CIPN.

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Section: Discussionmentioning

confidence: 76%

High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats

Meregalli

Marjanović

Scali

et al. 2018

J Neuroinflammation

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“…Notably, although the present study showed that the SIRT1 downregulation promoted the NALP1 expression, bortezomib did not decrease the SIRT1 binding at NALP1 promoter regions flanking the p-STAT3-binding site relative to the control group, suggested that the increases of NALP1 might not directly result from the reduced deacetylase activity following SIRT1 decrease induced by bortezomib. Our previous and peer’s studies showed that STAT3, a transcriptional factor, was involved in the neuropathic pain induced by nerve injury or chemotherapeutic drug [ 19 , 23 , 30 ]. Furthermore, studies showed that SIRT1 suppressed STAT3 phosphorylation, which promoted the transcription of gluconeogenic gene [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Bortezomib (Haoran Biological Technology CO, Shanghai) was intraperitoneally injected at 0.4 mg/kg once per day for consecutive 5 days as described previously [ 19 ]. Control animals received an equivalent volume of vehicle saline.…”

Section: Methodsmentioning

confidence: 99%

“…For intrathecal injection, after animals were anesthetized intraperitoneally with 50 mg/kg sodium pentobarbital, polyethylene intrathecal catheters (PE-10, Becton Dickinson, USA) were implanted into animals as described previously [ 19 ]. In brief, the catheter was inserted into the lumbar subarachnoid space between fifth and sixth lumbar vertebrae with the tip of the catheter located near the L5 spinal segmental level.…”

Section: Methodsmentioning

confidence: 99%

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Reduction of SIRT1 epigenetically upregulates NALP1 expression and contributes to neuropathic pain induced by chemotherapeutic drug bortezomib

Chen

Fan

Luo

et al. 2018

J Neuroinflammation

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BackgroundBortezomib is a frequently used chemotherapeutic drug for the treatment of multiple myeloma and other nonsolid malignancies. Accumulating evidence has demonstrated that bortezomib-induced persistent pain serves as the most frequent reason for treatment discontinuation.MethodsThe von Frey test was performed to evaluate neuropathic pain behavior, and real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, western blot, immunohistochemistry, and small interfering RNA were performed to explore the molecular mechanisms in adult male Sprague-Dawley rats.ResultsWe found that application of bortezomib significantly increased the expression of NALP1 protein and mRNA levels in spinal dorsal horn neurons, and intrathecal application of NALP1 siRNA attenuated the bortezomib-induced mechanical allodynia. In addition, bortezomib also decreased the SIRT1 expression, and treatment with SIRT1 activator resveratrol ameliorated the NALP1 upregulation and mechanical allodynia induced by bortezomib. Meanwhile, knockdown of SIRT1 using the SIRT1 siRNA induced the NALP1 upregulation in dorsal horn and mechanical allodynia in normal animal. These results suggested that reduction of SIRT1 induced the NALP1 upregulation in dorsal horn neurons, and participated in bortezomib-induced mechanical allodynia. Importantly, we found that the binding of SIRT1 and NALP1 promoter region did not change before and after bortezomib treatment, but SIRT1 downregulation increased p-STAT3 expression. Furthermore, the activation of STAT3 enhanced the recruitment of p-STAT3 to the Nalp1 gene promoter, which increased the acetylation of histone H3 and H4 in NALP1 promoter regions and epigenetically upregulated NALP1 expression in the rodents with bortezomib treatment.ConclusionThese findings suggested a new epigenetic mechanism for NALP1 upregulation involving SIRT1 reduction and subsequent STAT3-mediated histone hyperacetylation in NALP1 promoter region in dorsal horn neurons, which contributed to the bortezomib-induced mechanical allodynia.

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“…These actions of EX-527 were reversed by S3I-201 ( Figure 6D,E). Bortezomib represses SIRT1 expression and increases the activity of STAT3 [48,49]. We also found that the amount of SSEA3, sialyl Lewis a, and B3GALT5-LTR promoter activity was reduced by bortezomib ( Figure 6F-H), and the bortezomib-mediated repression of SSEA3, sialyl Lewis a, and B3GALT5-LTR promoter was reversed by Stattic, another STAT3 inhibitor.…”

Section: Ra-mediated Sirt1-stat3 Pathway Regulates B3galt5-ltr Promotmentioning

confidence: 53%

SSEA3 and Sialyl Lewis a Glycan Expression Is Controlled by B3GALT5 LTR through Lamin A-NFYA and SIRT1-STAT3 Signaling in Human ES Cells

Cai

Lee

Chou

et al. 2020

Cells

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B3GALT5 is involved in the synthesis of embryonic stem (ES) cell marker glycan, stage-specific embryonic antigen-3 (SSEA3). This gene has three native promoters and an integrated retroviral long terminal repeat (LTR) promoter. We found that B3GALT5-LTR is expressed at high levels in human ES cells. B3GALT5-LTR is also involved in the synthesis of the cancer-associated glycan, sialyl Lewis a. Sialyl Lewis a is expressed in ES cells and its expression decreases upon differentiation. Retinoic acid induced differentiation of ES cells, decreased the short form of NFYA (NFYAs), increased phosphorylation of STAT3, and decreased B3GALT5-LTR expression. NFYAs activated, and constitutively-active STAT3 (STAT3C) repressed B3GALT5-LTR promoter. The NFYAs and STAT3C effects were eliminated when their binding sites were deleted. Retinoic acid decreased the binding of NFYA to B3GALT5-LTR promoter and increased phospho-STAT3 binding. Lamin A repressed NFYAs and SSEA3 expression. SSEA3 repression mediated by a SIRT1 inhibitor was reversed by a STAT3 inhibitor. Repression of SSEA3 and sialyl Lewis a synthesis mediated by retinoic acid was partially reversed by lamin A short interfering RNA (siRNA) and a STAT3 inhibitor. In conclusion, B3GALT5-LTR is regulated by lamin A-NFYA and SIRT1-STAT3 signaling that regulates SSEA3 and sialyl Lewis a synthesis in ES cells, and sialyl Lewis a is also a ES cell marker.

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Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib

Cited by 71 publications

References 44 publications

High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats

High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats

Reduction of SIRT1 epigenetically upregulates NALP1 expression and contributes to neuropathic pain induced by chemotherapeutic drug bortezomib

SSEA3 and Sialyl Lewis a Glycan Expression Is Controlled by B3GALT5 LTR through Lamin A-NFYA and SIRT1-STAT3 Signaling in Human ES Cells

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