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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2021

Open Access 01-12-2021 | Neuropathic Pain | Research

Transcriptome profiling of long noncoding RNAs and mRNAs in spinal cord of a rat model of paclitaxel-induced peripheral neuropathy identifies potential mechanisms mediating neuroinflammation and pain

Authors: Yuanyuan Li, Chengyu Yin, Boyu Liu, Huimin Nie, Jie Wang, Danyi Zeng, Ruixiang Chen, Xiaofen He, Junfan Fang, Junying Du, Yi Liang, Yongliang Jiang, Jianqiao Fang, Boyi Liu

Published in: Journal of Neuroinflammation | Issue 1/2021

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Abstract

Background

Paclitaxel is a widely prescribed chemotherapy drug for treating solid tumors. However, paclitaxel-induced peripheral neuropathy (PIPN) is a common adverse effect during paclitaxel treatment, which results in sensory abnormalities and neuropathic pain among patients. Unfortunately, the mechanisms underlying PIPN still remain poorly understood. Long noncoding RNAs (lncRNAs) are novel and promising targets for chronic pain treatment, but their involvement in PIPN still remains unexplored.

Methods

We established a rat PIPN model by repetitive paclitaxel application. Immunostaining, RNA sequencing (RNA-Seq) and bioinformatics analysis were performed to study glia cell activation and explore lncRNA/mRNA expression profiles in spinal cord dorsal horn (SCDH) of PIPN model rats. qPCR and protein assay were used for further validation.

Results

PIPN model rats developed long-lasting mechanical and thermal pain hypersensitivities in hind paws, accompanied with astrocyte and microglia activation in SCDH. RNA-Seq identified a total of 814 differentially expressed mRNAs (DEmRNA) (including 467 upregulated and 347 downregulated) and 412 DElncRNAs (including 145 upregulated and 267 downregulated) in SCDH of PIPN model rats vs. control rats. Functional analysis of DEmRNAs and DElncRNAs identified that the most significantly enriched pathways include immune/inflammatory responses and neurotrophin signaling pathways, which are all important mechanisms mediating neuroinflammation, central sensitization, and chronic pain. We further compared our dataset with other published datasets of neuropathic pain and identified a core set of immune response-related genes extensively involved in PIPN and other neuropathic pain conditions. Lastly, a competing RNA network analysis of DElncRNAs and DEmRNAs was performed to identify potential regulatory networks of lncRNAs on mRNA through miRNA sponging.

Conclusions

Our study provided the transcriptome profiling of DElncRNAs and DEmRNAs and uncovered immune and inflammatory responses were predominant biological events in SCDH of the rat PIPN model. Thus, our study may help to identify promising genes or signaling pathways for PIPN therapeutics.
Appendix
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Literature
1.
Banach M, Juranek JK, Zygulska AL. Chemotherapy-induced neuropathies-a growing problem for patients and health care providers. Brain Behav. 2017;7(1):e00558.PubMedCrossRef
2.
Mody MD, Gill HS, Saba NF. The evolving and future role of taxanes in squamous cell carcinomas of the head and neck: a review. JAMA Otolaryngol Head Neck Surg. 2016;142(9):898–905.PubMedCrossRef
3.
Fojo T, Menefee M. Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents. Ann Oncol. 2007;18(Suppl 5):v3–8.PubMedCrossRef
4.
5.
Brewer JR, Morrison G, Dolan ME, Fleming GF. Chemotherapy-induced peripheral neuropathy: current status and progress. Gynecol Oncol. 2016;140(1):176–83.PubMedCrossRef
6.
Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM, Heimans JJ. Paclitaxel-induced neuropathy. Ann Oncol. 1995;6(5):489–94.PubMedCrossRef
7.
Meng J, Zhang Q, Yang C, Xiao L, Xue Z, Zhu J. Duloxetine, a balanced serotonin-norepinephrine reuptake inhibitor, improves painful chemotherapy-induced peripheral neuropathy by inhibiting activation of p38 MAPK and NF-κB. Front Pharmacol. 2019;10:365.PubMedPubMedCentralCrossRef
8.
da Costa R, Passos GF, Quintao NLM, Fernandes ES, Maia J, Campos MM, et al. Taxane-induced neurotoxicity: pathophysiology and therapeutic perspectives. Br J Pharmacol. 2020;177(14):3127–46.PubMedCrossRefPubMedCentral
9.
Flatters SJL, Dougherty PM, Colvin LA. Clinical and preclinical perspectives on chemotherapy-induced peripheral neuropathy (CIPN): a narrative review. Br J Anaesth. 2017;119(4):737–49.PubMedCrossRef
10.
Sisignano M, Baron R, Scholich K, Geisslinger G. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol. 2014;10(12):694–707.PubMedCrossRef
11.
Li Y, Yin C, Li X, Liu B, Wang J, Zheng X, et al. Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons. Int J Mol Sci. 2019;20(23):5917.PubMedCentralCrossRef
12.
Yan X, Li F, Maixner DW, Yadav R, Gao M, Ali MW, et al. Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome. Glia. 2019;67(3):482–97.PubMedCrossRef
13.
Liu X, Tonello R, Ling Y, Gao YJ, Berta T. Paclitaxel-activated astrocytes produce mechanical allodynia in mice by releasing tumor necrosis factor-α and stromal-derived cell factor 1. J Neuroinflammation. 2019;16(1):209.PubMedPubMedCentralCrossRef
14.
Luo H, Liu HZ, Zhang WW, Matsuda M, Lv N, Chen G, et al. Interleukin-17 regulates neuron-glial communications, synaptic transmission, and neuropathic pain after chemotherapy. Cell Rep. 2019;29(8):2384–97.e5.PubMedCrossRef
15.
Yang C, Wu K, Wang S, Wei G. Long non-coding RNA XIST promotes osteosarcoma progression by targeting YAP via miR-195-5p. J Cell Biochem. 2018;119(7):5646–56.PubMedCrossRef
16.
She K, Yan H, Huang J, Zhou H, He J. miR-193b availability is antagonized by LncRNA-SNHG7 for FAIM2-induced tumour progression in non-small cell lung cancer. Cell Prolif. 2018;51(1):e12406.CrossRef
17.
Wu S, Bono J, Tao YX. Long noncoding RNA (lncRNA): a target in neuropathic pain. Expert Opin Ther Targets. 2019;23(1):15–20.PubMedCrossRef
18.
Briggs JA, Wolvetang EJ, Mattick JS, Rinn JL, Barry G. Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron. 2015;88(5):861–77.PubMedCrossRef
19.
Baskozos G, Dawes JM, Austin JS, Antunes-Martins A, McDermott L, Clark AJ, et al. Comprehensive analysis of long noncoding RNA expression in dorsal root ganglion reveals cell-type specificity and dysregulation after nerve injury. Pain. 2019;160(2):463–85.PubMedCrossRef
20.
Zhao X, Tang Z, Zhang H, Atianjoh FE, Zhao JY, Liang L, et al. A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci. 2013;16(8):1024–31.PubMedPubMedCentralCrossRef
21.
Wang S, Xu H, Zou L, Xie J, Wu H, Wu B, et al. LncRNA uc.48+ is involved in diabetic neuropathic pain mediated by the P2X3 receptor in the dorsal root ganglia. Purinergic Signal. 2016;12(1):139–48.PubMedCrossRef
22.
Yu W, Zhao GQ, Cao RJ, Zhu ZH, Li K. LncRNA NONRATT021972 was associated with neuropathic pain scoring in patients with type 2 diabetes. Behav Neurol. 2017;2017:2941297.PubMedPubMedCentralCrossRef
23.
Li Z, Li X, Chen X, Li S, Ho IHT, Liu X, et al. Emerging roles of long non-coding RNAs in neuropathic pain. Cell Prolif. 2019;52(1):e12528.PubMedCrossRef
24.
Zhang H, Li Y, de Carvalho-Barbosa M, Kavelaars A, Heijnen CJ, Albrecht PJ, et al. Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy. J Pain. 2016;17(7):775–86.PubMedPubMedCentralCrossRef
25.
Polomano RC, Mannes AJ, Clark US, Bennett GJ. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain. 2001;94(3):293–304.PubMedCrossRef
26.
Yin C, Hu Q, Liu B, Tai Y, Zheng X, Li Y, et al. Transcriptome profiling of dorsal root ganglia in a rat model of complex regional pain syndrome type-I reveals potential mechanisms involved in pain. J Pain Res. 2019;12:1201–16.PubMedPubMedCentralCrossRef
27.
Chai W, Tai Y, Shao X, Liang Y, Zheng GQ, Wang P, et al. Electroacupuncture alleviates pain responses and inflammation in a rat model of acute gout arthritis. Evid Based Complement Alternat Med. 2018;2018:2598975.PubMedPubMedCentralCrossRef
28.
Dixon WJ. Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol. 1980;20:441–62.PubMedCrossRef
29.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55–63.PubMedCrossRef
30.
Hu Q, Wang Q, Wang C, Tai Y, Liu B, Shao X, et al. TRPV1 channel contributes to the behavioral hypersensitivity in a rat model of complex regional pain syndrome type 1. Front Pharmacol. 2019;10:453.PubMedPubMedCentralCrossRef
31.
Li R, Li Y, Kristiansen K, Wang J. SOAP: short oligonucleotide alignment program. Bioinformatics (Oxford, England). 2008;24(5):713–4.CrossRef
32.
33.
Benelli M, Pescucci C, Marseglia G, Severgnini M, Torricelli F, Magi A. Discovering chimeric transcripts in paired-end RNA-seq data by using EricScript. Bioinformatics (Oxford, England). 2012;28(24):3232–9.CrossRef
34.
Shen S, Park JW, Lu ZX, Lin L, Henry MD, Wu YN, et al. rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc Natl Acad Sci U S A. 2014;111(51):E5593–601.PubMedPubMedCentralCrossRef
35.
36.
37.
38.
Chen W, Ding H, Zhou X, Lin H, Chou KC. iRNA(m6A)-PseDNC: identifying N(6)-methyladenosine sites using pseudo dinucleotide composition. Anal Biochem. 2018;561-562:59–65.PubMedCrossRef
39.
Liu B, Tai Y, Liu B, Caceres AI, Yin C, Jordt SE. Transcriptome profiling reveals Th2 bias and identifies endogenous itch mediators in poison ivy contact dermatitis. JCI Insight. 2019;5(14):e124497.CrossRef
40.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif). 2001;25(4):402–8.CrossRef
41.
Yin C, Liu B, Li Y, Li X, Wang J, Chen R, et al. IL-33/ST2 induces neutrophil-dependent reactive oxygen species production and mediates gout pain. Theranostics. 2020;10(26):12189–203.PubMedPubMedCentralCrossRef
42.
Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41(Database issue):D808–15.PubMed
43.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.PubMedPubMedCentralCrossRef
44.
Wu J, Hocevar M, Bie B, Foss JF, Naguib M. Cannabinoid type 2 receptor system modulates paclitaxel-induced microglial dysregulation and central sensitization in rats. J Pain. 2019;20(5):501–14.PubMedCrossRef
45.
Peters CM, Jimenez-Andrade JM, Jonas BM, Sevcik MA, Koewler NJ, Ghilardi JR, et al. Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Exp Neurol. 2007;203(1):42–54.PubMedCrossRef
46.
47.
Hu Q, Zheng X, Li X, Liu B, Yin C, Li Y, et al. Electroacupuncture alleviates mechanical allodynia in a rat model of complex regional pain syndrome type-I via suppressing spinal CXCL12/CXCR4 signaling. J Pain. 2020;21(9-10):1060–74.PubMedCrossRef
48.
Donnelly CR, Andriessen AS, Chen G, Wang K, Jiang C, Maixner W, et al. Central nervous system targets: glial cell mechanisms in chronic pain. Neurotherapeutics. 2020;17(3):846–60.PubMedCrossRefPubMedCentral
49.
Zhao YX, Yao MJ, Liu Q, Xin JJ, Gao JH, Yu XC. Electroacupuncture treatment attenuates paclitaxel-induced neuropathic pain in rats via inhibiting spinal glia and the TLR4/NF-kappaB pathway. J Pain Res. 2020;13:239–50.PubMedPubMedCentralCrossRef
50.
Wang J, Jiang C, Ba X, Yang S, Wu J, Huang Z, et al. Selective activation of metabotropic glutamate receptor 7 blocks paclitaxel-induced acute neuropathic pain and suppresses spinal glial reactivity in rats. Psychopharmacology (Berl). 2021;238(1):107–19.
51.
Beh ST, Kuo YM, Chang WW, Wilder-Smith E, Tsao CH, Tsai CH, et al. Preventive hypothermia as a neuroprotective strategy for paclitaxel-induced peripheral neuropathy. Pain. 2019;160(7):1505–21.PubMedCrossRef
52.
Liu X, Tonello R, Ling Y, Gao YJ, Berta T. Paclitaxel-activated astrocytes produce mechanical allodynia in mice by releasing tumor necrosis factor-alpha and stromal-derived cell factor 1. J Neuroinflammation. 2019;16(1):209.PubMedPubMedCentralCrossRef
53.
Saika F, Matsuzaki S, Kobayashi D, Ideguchi Y, Nakamura TY, Kishioka S, et al. Chemogenetic regulation of CX3CR1-expressing microglia using Gi-DREADD exerts sex-dependent anti-allodynic effects in mouse models of neuropathic pain. Front Pharmacol. 2020;11:925.PubMedPubMedCentralCrossRef
54.
Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science (New York, NY). 2016;354(6312):572–7.CrossRef
55.
Jiang BC, Liu T, Gao YJ. Chemokines in chronic pain: cellular and molecular mechanisms and therapeutic potential. Pharmacol Ther. 2020;212:107581.PubMedCrossRef
56.
Chen SP, Zhou YQ, Liu DQ, Zhang W, Manyande A, Guan XH, et al. PI3K/Akt pathway: a potential therapeutic target for chronic pain. Curr Pharm Des. 2017;23(12):1860–8.PubMedCrossRef
57.
Guan X, Fu Q, Xiong B, Song Z, Shu B, Bu H, et al. Activation of PI3Kgamma/Akt pathway mediates bone cancer pain in rats. J Neurochem. 2015;134(3):590–600.PubMedCrossRef
58.
Javeed A, Ashraf M, Riaz A, Ghafoor A, Afzal S, Mukhtar MM. Paclitaxel and immune system. Eur J Pharm Sci. 2009;38(4):283–90.PubMedCrossRef
59.
Zeng QZ, Yang F, Li CG, Xu LH, He XH, Mai FY, et al. Paclitaxel enhances the innate immunity by promoting NLRP3 inflammasome activation in macrophages. Front Immunol. 2019;10:72.PubMedPubMedCentralCrossRef
60.
Wanderley CW, Colón DF, Luiz JPM, Oliveira FF, Viacava PR, Leite CA, et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res. 2018;78(20):5891–900.PubMed
61.
Ochi-ishi R, Nagata K, Inoue T, Tozaki-Saitoh H, Tsuda M, Inoue K. Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia. Mol Pain. 2014;10:53.PubMedPubMedCentralCrossRef
62.
Jiang BC, Cao DL, Zhang X, Zhang ZJ, He LN, Li CH, et al. CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. J Clin Invest. 2016;126(2):745–61.PubMedPubMedCentralCrossRef
63.
Liu S, Liu X, Xiong H, Wang W, Liu Y, Yin L, et al. CXCL13/CXCR5 signaling contributes to diabetes-induced tactile allodynia via activating pERK, pSTAT3, pAKT pathways and pro-inflammatory cytokines production in the spinal cord of male mice. Brain Behav Immun. 2019;80:711–24.PubMedCrossRef
64.
Chen R, Yin C, Hu Q, Liu B, Tai Y, Zheng X, et al. Expression profiling of spinal cord dorsal horn in a rat model of complex regional pain syndrome type-I uncovers potential mechanisms mediating pain and neuroinflammation responses. J Neuroinflammation. 2020;17(1):162.PubMedPubMedCentralCrossRef
65.
66.
Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17(1):47–62.CrossRefPubMed
67.
Li G, Jiang H, Zheng C, Zhu G, Xu Y, Sheng X, et al. Long noncoding RNA MRAK009713 is a novel regulator of neuropathic pain in rats. Pain. 2017;158(10):2042–52.PubMedCrossRef
68.
Wen J, Yang Y, Wu S, Wei G, Jia S, Hannaford S, et al. Long noncoding RNA H19 in the injured dorsal root ganglion contributes to peripheral nerve injury-induced pain hypersensitivity. Transl Perioper Pain Med. 2020;7(2):176–84.PubMedPubMedCentral
69.
Jiang BC, Sun WX, He LN, Cao DL, Zhang ZJ, Gao YJ. Identification of lncRNA expression profile in the spinal cord of mice following spinal nerve ligation-induced neuropathic pain. Mol Pain. 2015;11:43.PubMedPubMedCentralCrossRef
70.
Duran RC, Yan H, Zheng Y, Huang X, Grill R, Kim DH, et al. The systematic analysis of coding and long non-coding RNAs in the sub-chronic and chronic stages of spinal cord injury. Sci Rep. 2017;7:41008.PubMedPubMedCentralCrossRef
71.
Zhou J, Fan Y, Chen H. Analyses of long non-coding RNA and mRNA profiles in the spinal cord of rats using RNA sequencing during the progression of neuropathic pain in an SNI model. RNA Biol. 2017;14(12):1810–26.PubMedPubMedCentralCrossRef
72.
Ray P, Torck A, Quigley L, Wangzhou A, Neiman M, Rao C, et al. Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research. Pain. 2018;159(7):1325–45.PubMedPubMedCentralCrossRef
73.
74.
Wang GJ, Zhang X, Huang LD, Xiao Y. Involvement of the sodium channel Nav1.7 in paclitaxel-induced peripheral neuropathy through ERK1/2 signaling in rats. Curr Neurovasc Res. 2020;17(3):267–74.
75.
Zhao YX, Yao MJ, Liu Q, Xin JJ, Gao JH, Yu XC. Electroacupuncture treatment attenuates paclitaxel-induced neuropathic pain in rats via inhibiting spinal glia and the TLR4/NF-κB pathway. J Pain Res. 2020;13:239–50.PubMedPubMedCentralCrossRef
76.
Gelderblom H, Verweij J, Nooter K, Sparreboom A, Cremophor EL. The drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590–8.PubMedCrossRef
77.
Jia M, Wu C, Gao F, Xiang H, Sun N, Peng P, et al. Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain. Mol Pain. 2017;13:1744806917719804.PubMedCrossRef
78.
Manjavachi MN, Passos GF, Trevisan G, Araújo SB, Pontes JP, Fernandes ES, et al. Spinal blockage of CXCL1 and its receptor CXCR2 inhibits paclitaxel-induced peripheral neuropathy in mice. Neuropharmacology. 2019;151:136–43.PubMedCrossRef
79.
Li D, Huang ZZ, Ling YZ, Wei JY, Cui Y, Zhang XZ, et al. Up-regulation of CX3CL1 via nuclear factor-kappaB-dependent histone acetylation is involved in paclitaxel-induced peripheral neuropathy. Anesthesiology. 2015;122(5):1142–51.PubMedCrossRef
Metadata
Title
Transcriptome profiling of long noncoding RNAs and mRNAs in spinal cord of a rat model of paclitaxel-induced peripheral neuropathy identifies potential mechanisms mediating neuroinflammation and pain
Authors
Yuanyuan Li
Chengyu Yin
Boyu Liu
Huimin Nie
Jie Wang
Danyi Zeng
Ruixiang Chen
Xiaofen He
Junfan Fang
Junying Du
Yi Liang
Yongliang Jiang
Jianqiao Fang
Boyi Liu
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2021
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-021-02098-y

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