Top

Journal of Neuroinflammation

Published in:

Open Access 01-12-2018 | Research

Chronic constriction injury-induced microRNA-146a-5p alleviates neuropathic pain through suppression of IRAK1/TRAF6 signaling pathway

Authors: Zhiyao Wang, Fan Liu, Min Wei, Yue Qiu, Chao Ma, Le Shen, Yuguang Huang

Published in: Journal of Neuroinflammation | Issue 1/2018

Abstract

Background

microRNA-146a-5p (miRNA-146a-5p) is a key molecule in the negative regulation pathway of TLRs and IL-1 receptor (TIR) signaling. Our recent study demonstrated that MyD88-dependent signaling pathway of TIR in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) plays a role in peripheral nerve injury-induced neuropathic pain. However, it was not clear whether and how miRNA-146a-5p regulates the TIR pathway of DRG and SDH in the development of neuropathic pain.

Methods

The sciatic nerve chronic constriction injury (CCI) model of rat was used to induce chronic neuropathic pain. The levels and cellular distribution of miRNA-146a-5p were detected with quantitative real-time PCR (qPCR) and fluorescent in situ hybridization (FISH). The RNA level, protein level, and cellular distribution of IRAK1 and TRAF6 that is targeted by miRNA-146a-5p were detected with qPCR, western blot, and immunofluorescent. The pain-related behavioral effect of miRNA-146a-5p was accessed after intrathecal administration. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia.

Results

We found that the level of miRNA-146a-5p significantly increased in L4-L6 DRGs and SDH after CCI surgery; meanwhile, the protein level of IRAK1 and TRAF6 in DRGs was significantly increased after CCI. Intrathecal injection of miR146a-5p agomir or miRNA-146a-5p antagomir regulates miRNA-146a-5p level of L4-L6 DRGs and SDH. We found that intrathecal injection of miR146a-5p agomir can alleviate mechanical and thermal hyperalgesia in CCI rats and reverse the upregulation of IRAK1 and TRAF6 of L4-L6 DRGs and SDH induced by CCI. We furthermore found that intrathecal injection of miRNA-146a-5p antagomir can exacerbate the mechanical and thermal pain-related behavior of CCI rats and meanwhile increase IRAK1 and TRAF6 of L4-L6 DRGs and SDH expression even further.

Conclusions

miRNA-146a-5p of DRG and SDH can modulate the development of CCI-induced neuropathic pain through inhibition of IRAK1 and TRAF6 in the TIR signaling pathway. Hence, miRNA-146a-5p may serve as a potential therapeutic target for neuropathic pain.

Available only for authorised users

Haanpaa M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, Cruccu G, Hansson P, Haythornthwaite JA, Iannetti GD, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152(1):14–27.CrossRefPubMed

Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002.CrossRefPubMedPubMedCentral

Finnerup NB, Haroutounian S, Kamerman P, Baron R, Bennett DLH, Bouhassira D, Cruccu G, Freeman R, Hansson P, Nurmikko T, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain. 2016;157(8):1599–606.CrossRefPubMedPubMedCentral

Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2–15.CrossRefPubMed

Bettoni I, Comelli F, Rossini C, Granucci F, Giagnoni G, Peri F, Costa B. Glial TLR4 receptor as new target to treat neuropathic pain: efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice. Glia. 2008;56(12):1312–9.CrossRefPubMed

Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundback P, Palmblad K, Andersson U, Harris H, Svensson CI. Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain. 2014;155(9):1802–13.CrossRefPubMed

Li Y, Zhang H, Zhang H, Kosturakis AK, Jawad AB, Dougherty PM. Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain. 2014;15(7):712–25.CrossRefPubMedPubMedCentral

Lim H, Kim D, Lee SJ. Toll-like receptor 2 mediates peripheral nerve injury-induced NADPH oxidase 2 expression in spinal cord microglia. J Biol Chem. 2013;288(11):7572–9.CrossRefPubMedPubMedCentral

Peirs C, Seal RP. Targeting toll-like receptors to treat chronic pain. Nat Med. 2015;21(11):1251–2.CrossRefPubMed

10.

Liu T, Han Q, Chen G, Huang Y, Zhao LX, Berta T, Gao YJ, Ji RR. Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain. 2016;157(4):806–17.CrossRefPubMedPubMedCentral

11.

Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011;34(5):269–81.CrossRefPubMedPubMedCentral

12.

Due MR, Piekarz AD, Wilson N, Feldman P, Ripsch MS, Chavez S, Yin H, Khanna R, White FA. Neuroexcitatory effects of morphine-3-glucuronide are dependent on toll-like receptor 4 signaling. J Neuroinflammation. 2012;9:200.CrossRefPubMedPubMedCentral

13.

Allette YM, Kim Y, Randolph AL, Smith JA, Ripsch MS, White FA. Decoy peptide targeted to toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons. Sci Rep. 2017;7(1):3741.CrossRefPubMedPubMedCentral

14.

Diogenes A, Ferraz CC, Akopian AN, Henry MA, Hargreaves KM. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res. 2011;90(6):759–64.CrossRefPubMed

15.

Liu F, Wang Z, Qiu Y, Wei M, Li C, Xie Y, Shen L, Huang Y, Ma C. Suppression of MyD88-dependent signaling alleviates neuropathic pain induced by peripheral nerve injury in the rat. J Neuroinflammation. 2017;14(1):70.CrossRefPubMedPubMedCentral

16.

O'Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in toll-like receptor signalling. Nat Rev Immunol. 2007;7(5):353–64.CrossRefPubMed

17.

Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103(33):12481–6.CrossRefPubMedPubMedCentral

18.

Ma X, Becker Buscaglia LE, Barker JR, Li Y. MicroRNAs in NF-kappaB signaling. J Mol Cell Biol. 2011;3(3):159–66.CrossRefPubMedPubMedCentral

19.

Bali KK, Kuner R. Noncoding RNAs: key molecules in understanding and treating pain. Trends Mol Med. 2014;20(8):437–48.CrossRefPubMedPubMedCentral

20.

Lutz BM, Bekker A, Tao YX. Noncoding RNAs: new players in chronic pain. Anesthesiology. 2014;121(2):409–17.CrossRefPubMed

21.

Iyer A, Zurolo E, Prabowo A, Fluiter K, Spliet WG, van Rijen PC, Gorter JA, Aronica E. MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. PLoS One. 2012;7(9):e44789.CrossRefPubMedPubMedCentral

22.

Hou J, Wang P, Lin L, Liu X, Ma F, An H, Wang Z, Ca X. MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol. 2009;183(3):2150–8.CrossRefPubMed

23.

Chassin C, Hempel C, Stockinger S, Dupont A, Kubler JF, Wedemeyer J, Vandewalle A, Hornef MW. MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury. EMBO Mol Med. 2012;4(12):1308–19.CrossRefPubMedPubMedCentral

24.

Rusca N, Monticelli S. MiR-146a in immunity and disease. Mol Biol Int. 2011;2011:437301.CrossRefPubMedPubMedCentral

25.

Li X, Kroin JS, Kc R, Gibson G, Chen D, Corbett GT, Pahan K, Fayyaz S, Kim JS, van Wijnen AJ, et al. Altered spinal microRNA-146a and the microRNA-183 cluster contribute to osteoarthritic pain in knee joints. J Bone Mineral Res. 2013;28(12):2512–22.CrossRef

26.

Lu Y, Cao D-L, Jiang B-C, Yang T, Gao Y-J. MicroRNA-146a-5p attenuates neuropathic pain via suppressing TRAF6 signaling in the spinal cord. Brain Behav Immun. 2015;49:119–29.CrossRefPubMed

27.

Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87–107.CrossRefPubMed

28.

Lin C-R, Amaya F, Barrett L, Wang H, Takada J, Samad TA, Woolf CJ. Prostaglandin E-2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther. 2006;319(3):1096–103.CrossRefPubMed

29.

Qiu Y, Chen WY, Wang ZY, Liu F, Wei M, Ma C, Huang YG. Simvastatin attenuates neuropathic pain by inhibiting the RhoA/LIMK/cofilin pathway. Neurochem Res. 2016;41(9):2457–69.CrossRefPubMed

30.

Wei J, Wang J, Zhou Y, Yan S, Li K, Lin H. MicroRNA-146a contributes to SCI recovery via regulating TRAF6 and IRAK1 expression. Biomed Res Int. 2016;2016:4013487.PubMedPubMedCentral

31.

Li X, Gibson G, Kim J-S, Kroin J, Xu S, van Wijnen AJ, Im H-J. MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene. 2011;480(1–2):34–41.CrossRefPubMedPubMedCentral

32.

Favereaux A, Thoumine O, Bouali-Benazzouz R, Roques V, Papon MA, Salam SA, Drutel G, Leger C, Calas A, Nagy F, et al. Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain. EMBO J. 2011;30(18):3830–41.CrossRefPubMedPubMedCentral

33.

von Schack D, Agostino MJ, Murray BS, Li Y, Reddy PS, Chen J, Choe SE, Strassle BW, Li C, Bates B, et al. Dynamic changes in the microRNA expression profile reveal multiple regulatory mechanisms in the spinal nerve ligation model of neuropathic pain. PLoS One. 2011;6(3):e17670.CrossRefPubMedPubMedCentral

34.

Sengupta JN, Pochiraju S, Kannampalli P, Bruckert M, Addya S, Yadav P, Miranda A, Shaker R, Banerjee B. MicroRNA-mediated GABA Aalpha-1 receptor subunit down-regulation in adult spinal cord following neonatal cystitis-induced chronic visceral pain in rats. Pain. 2013;154(1):59–70.CrossRefPubMedPubMedCentral

35.

Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, Garcia-Flores Y, Luong M, Devrekanli A, Xu J, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208(6):1189–201.CrossRefPubMedPubMedCentral

36.

Villalba M, Hott M, Martin C, Aguila B, Valdivia S, Quezada C, Zambrano A, Concha MI, Otth C. Herpes simplex virus type 1 induces simultaneous activation of toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes. Med Microbiol Immunol. 2012;201(3):371–9.CrossRefPubMed

37.

Kim D, Kim MA, Cho I-H, Kim MS, Lee S, Jo E-K, Choi S-Y, Park K, Kim JS, Akira S, et al. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem. 2007;282(20):14975–83.CrossRefPubMed

38.

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.CrossRefPubMedPubMedCentral

39.

O'Neill LA, Sheedy FJ, McCoy CE. MicroRNAs: the fine-tuners of toll-like receptor signalling. Nat Rev Immunol. 2011;11(3):163–75.CrossRefPubMed

Title: Chronic constriction injury-induced microRNA-146a-5p alleviates neuropathic pain through suppression of IRAK1/TRAF6 signaling pathway
Authors: Zhiyao Wang
Fan Liu
Min Wei
Yue Qiu
Chao Ma
Le Shen
Yuguang Huang
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-018-1215-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Chronic constriction injury-induced microRNA-146a-5p alleviates neuropathic pain through suppression of IRAK1/TRAF6 signaling pathway

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy

Inflammatory and cytotoxic effects of bifenthrin in primary microglia and organotypic hippocampal slice cultures

Central intracrine DHEA synthesis in ageing-related neuroinflammation and neurodegeneration: therapeutic potential?

Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery—a randomized trial

Immunophenotyping of cerebrospinal fluid cells by Chipcytometry

Calcineurin A beta deficiency ameliorates HFD-induced hypothalamic astrocytosis in mice