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MicroRNAs in the Spinal Microglia Serve Critical Roles in Neuropathic Pain

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Abstract

Neuropathic pain (NP) can occur after peripheral nerve injury (PNI), and it can be converted into a maladaptive, detrimental phenotype that causes a long-term state of pain hypersensitivity. In the last decade, the discovery that dysfunctional microglia evoke pain, called “microgliopathic pain,” has challenged traditional neuronal views of “pain” and has been extensively explored. Recent studies have shown that microRNAs (miRNAs) can act as activators or inhibitors of spinal microglia in NP conditions. We first briefly review spinal microglial activation in NP. We then comprehensively describe miRNA expression changes and their potential mechanisms in the response of microglia to nerve injury. We summarize the roles of the following two representative miRNAs: miR-124, which reverses NP by keeping microglia quiescent, and miR-155, which promotes NP following microglial activation. Finally, we focused on the therapeutic potential of microglial miRNAs in NP. The findings we summarized may be essential tools for basic research and clinical treatment of NP.

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Abbreviations

NP:

Neuropathic pain

PNI:

Peripheral nerve injury

MiRNAs:

MicroRNAs

DRG:

Dorsal root ganglion

CNS:

Central nervous system

3′-UTRs:

3′-Untranslated regions

CR3:

Complement receptor 3

CD11b:

Cluster of differentiation 11b

Iba-1:

Ionized calcium-binding adaptor molecule 1

POD:

Postoperative day

SNL:

Spinal nerve ligation

SNT:

Sciatic nerve transection

SCI:

Spinal cord injury

CCI:

Chronic constriction injury

TLR:

Toll-like recepto

HDLs:

High-density lipoprotein

SOCS1:

Suppressor of cytokine signaling 1

NOX2:

NADPH oxidase

TNF:

Tumor necrosis factor

p38 MAPKs:

Phosphotyrosine 38 mitogen-activated protein kinases

References

  1. Zorina-Lichtenwalter K, Parisien M, Diatchenko L (2018) Genetic studies of human neuropathic pain conditions: a review. Pain 159(3):583–594. https://doi.org/10.1097/j.pain.0000000000001099

    Article  CAS  PubMed  Google Scholar 

  2. St John Smith E (2018) Advances in understanding nociception and neuropathic pain. J Neurol 265(2):231–238. https://doi.org/10.1007/s00415-017-8641-6

    Article  CAS  PubMed  Google Scholar 

  3. Murnion BP (2018) Neuropathic pain: current definition and review of drug treatment. Aust Prescr 41(3):60–63. https://doi.org/10.18773/austprescr.2018.022

    Article  PubMed  PubMed Central  Google Scholar 

  4. Machelska H, Celik MO (2016) Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics. F1000Res 5:2743. https://doi.org/10.12688/f1000research.9621.1

    Article  PubMed  PubMed Central  Google Scholar 

  5. Scholz J, Woolf CJ (2007) The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 10(11):1361–1368. https://doi.org/10.1038/nn1992

    Article  CAS  PubMed  Google Scholar 

  6. Gilmore SA (1975) Proliferation of non-neuronal cells in spinal cords of irradiated, immature rats following transection of the sciatic nerve. Anat Rec 181(4):799–811. https://doi.org/10.1002/ar.1091810411

    Article  CAS  PubMed  Google Scholar 

  7. Gilmore SA, Skinner RD (1979) Intraspinal non-neuronal cellular responses to peripheral nerve injury. Anat Rec 194(3):369–387. https://doi.org/10.1002/ar.1091940305

    Article  CAS  PubMed  Google Scholar 

  8. Raghavendra V, Tanga F, DeLeo JA (2003) Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 306(2):624–630. https://doi.org/10.1124/jpet.103.052407

    Article  CAS  PubMed  Google Scholar 

  9. Inoue K, Tsuda M (2018) Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 19(3):138–152. https://doi.org/10.1038/nrn.2018.2

    Article  CAS  PubMed  Google Scholar 

  10. Tsuda M (2016) Microglia in the spinal cord and neuropathic pain. J Diabetes Investig 7(1):17–26. https://doi.org/10.1111/jdi.12379

    Article  CAS  PubMed  Google Scholar 

  11. Mapplebeck JC, Beggs S, Salter MW (2017) Molecules in pain and sex: a developing story. Mol Brain 10(1):9. https://doi.org/10.1186/s13041-017-0289-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Su1 Z, Yang Z, Xu Y, Chen Y, Yu Q (2015) MicroRNAs in apoptosis, autophagy and necroptosis. Oncotarget 6:11

    Google Scholar 

  13. Bartel DP, Chen CZ (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5(5):396–400. https://doi.org/10.1038/nrg1328

    Article  CAS  PubMed  Google Scholar 

  14. Desvignes T, Batzel P, Berezikov E, Eilbeck K, Eppig JT, McAndrews MS, Singer A, Postlethwait JH (2015) miRNA nomenclature: a view incorporating genetic origins, biosynthetic pathways, and sequence variants. Trends Genet 31(11):613–626. https://doi.org/10.1016/j.tig.2015.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hu HY, Yan Z, Xu Y, Hu H, Menzel C, Zhou YH, Chen W, Khaitovich P (2009) Sequence features associated with microRNA strand selection in humans and flies. BMC Genomics 10:413. https://doi.org/10.1186/1471-2164-10-413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. https://doi.org/10.1016/j.cell.2009.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pan Z, Li GF, Sun ML, Xie L, Liu D, Zhang Q, Yang XX, Xia S et al (2019) MicroRNA-1224 splicing circularRNA-Filip1l in an Ago2-dependent manner regulates chronic inflammatory pain via targeting Ubr5. J Neurosci 39(11):2125–2143. https://doi.org/10.1523/JNEUROSCI.1631-18.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Peng C, Li L, Zhang M-D, Gonzales CB, Parisien M, Usoskin D, Abdo H, Furlan A, Häring M, Diatchenko L, Hökfelt T, Hjerling-Leffler J, Ernfors P, Belfer I, Lallemend F, Harkany T (2017) MiR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes. Science 16 (356(6343)):1168–1171

  19. Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H (2013) miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability. Brain 136(Pt 9):2738–2750. https://doi.org/10.1093/brain/awt191

    Article  PubMed  Google Scholar 

  20. Zhang SB, Lin SY, Liu M, Liu CC, Ding HH, Sun Y, Ma C, Guo RX et al (2019) CircAnks1a in the spinal cord regulates hypersensitivity in a rodent model of neuropathic pain. Nat Commun 10(1):4119. https://doi.org/10.1038/s41467-019-12049-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang ZJ, Guo JS, Li SS, Wu XB, Cao DL, Jiang BC, Jing PB, Bai XQ et al (2018) TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. J Exp Med 215(12):3019–3037. https://doi.org/10.1084/jem.20180800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jiang BC, Cao DL, Zhang X, Zhang ZJ, He LN, Li CH, Zhang WW, Wu XB et al (2016) CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. J Clin Invest 126(2):745–761. https://doi.org/10.1172/JCI81950

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tozaki-Saitoh H, Masuda J, Kawada R, Kojima C, Yoneda S, Masuda T, Inoue K, Tsuda M (2018) Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development. Glia 67:1–12. https://doi.org/10.1002/glia.23570

    Article  Google Scholar 

  24. Eccleston C, Crombez G (2017) Advancing psychological therapies for chronic pain. F1000Res 6:461. doi:10.12688/f1000research.10612.1

  25. Schmidt MF (2017) miRNA targeting drugs: the next blockbusters? Methods Mol Biol 1517:3–22

    Article  CAS  PubMed  Google Scholar 

  26. Schmidt MF (2014) Drug target miRNAs: chances and challenges. Trends Biotechnol 32(11):578–585. https://doi.org/10.1016/j.tibtech.2014.09.002

    Article  CAS  PubMed  Google Scholar 

  27. Song G, Yang Z, Guo J, Zheng Y, Su X, Wang X (2020) Interactions among lncRNAs/circRNAs, miRNAs, and mRNAs in neuropathic pain. Neurotherapeutics. https://doi.org/10.1007/s13311-020-00881-y

  28. Kalpachidou T, Kummer KK, Kress M (2020) Non-coding RNAs in neuropathic pain. Neuronal Signal 4(1):NS20190099. https://doi.org/10.1042/NS20190099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Andersen HH, Duroux M, Gazerani P (2014) MicroRNAs as modulators and biomarkers of inflammatory and neuropathic pain conditions. Neurobiol Dis 71:159–168. https://doi.org/10.1016/j.nbd.2014.08.003

    Article  CAS  PubMed  Google Scholar 

  30. Jiangpan P, Qingsheng M, Zhiwen Y, Tao Z (2016) Emerging role of microRNA in neuropathic pain. Curr Drug Metab 17:336–344

    Article  PubMed  Google Scholar 

  31. Wake H, Fields RD (2011) Physiological function of microglia. Neuron Glia Biol 7(1):1–3. https://doi.org/10.1017/S1740925X12000166

    Article  PubMed  PubMed Central  Google Scholar 

  32. Narita M, Yoshida T, Nakajima M, Narita M, Miyatake M, Takagi T, Yajima Y, Suzuki T (2006) Direct evidence for spinal cord microglia in the development of a neuropathic pain-like state in mice. J Neurochem 97(5):1337–1348. https://doi.org/10.1111/j.1471-4159.2006.03808.x

    Article  CAS  PubMed  Google Scholar 

  33. Zhou Y, Li N, Zhu L, Lin Y, Cheng H (2018) The microglial activation profile and associated factors after experimental spinal cord injury in rats. Neuropsychiatr Dis Treat 14:2401–2413. https://doi.org/10.2147/NDT.S169940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gu N, Peng J, Murugan M, Wang X, Eyo UB, Sun D, Ren Y, DiCicco-Bloom E et al (2016) Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivity after peripheral nerve injury. Cell Rep 16(3):605–614. https://doi.org/10.1016/j.celrep.2016.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Calvo M, Bennett DL (2012) The mechanisms of microgliosis and pain following peripheral nerve injury. Exp Neurol 234(2):271–282. https://doi.org/10.1016/j.expneurol.2011.08.018

    Article  CAS  PubMed  Google Scholar 

  36. Masuda T, Tsuda M (2016) Inoue K (2015) Transcriptional regulation in microglia and neuropathic pain. Pain Manag 6(2):91–94

    Article  PubMed  Google Scholar 

  37. Jeong H, Na YJ, Lee K, Kim YH, Lee Y, Kang M, Jiang BC, Yeom YI et al (2016) High-resolution transcriptome analysis reveals neuropathic pain gene-expression signatures in spinal microglia after nerve injury. Pain 157(4):964–976. https://doi.org/10.1097/j.pain.0000000000000470

    Article  CAS  PubMed  Google Scholar 

  38. Denk F, Crow M, Didangelos A, Lopes Douglas M, McMahon Stephen B (2016) Persistent alterations in microglial enhancers in a model of chronic pain. Cell Rep 15(8):1771–1781. https://doi.org/10.1016/j.celrep.2016.04.063

    Article  CAS  PubMed  Google Scholar 

  39. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143. https://doi.org/10.1038/nn.3599

    Article  CAS  PubMed  Google Scholar 

  40. Young K, Morrison H (2018) Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ. J Vis Exp 136. https://doi.org/10.3791/57648

  41. Otxoa-de-Amezaga A, Miro-Mur F, Pedragosa J, Gallizioli M, Justicia C, Gaja-Capdevila N, Ruiz-Jaen F, Salas-Perdomo A et al (2019) Microglial cell loss after ischemic stroke favors brain neutrophil accumulation. Acta Neuropathol 137(2):321–341. https://doi.org/10.1007/s00401-018-1954-4

    Article  CAS  PubMed  Google Scholar 

  42. Sabirzhanov B, Li Y, Coll-Miro M, Matyas JJ, He J, Kumar A, Ward N, Yu J, Faden AI, Wu J (2019) Inhibition of NOX2 signaling limits pain-related behavior and improves motor function in male mice after spinal cord injury: participation of IL-10/miR-155 pathways. Brain Behav Immun:1–15. https://doi.org/10.1016/j.bbi.2019.02.024

  43. Tingfei Yan FZ, Sun C, Sun J, Wang Y, Xu X, Shi J, Shi G (2017) miR-32-5p-mediated Dusp5 downregulation contributes to neuropathic pain. Biochem Biophys Res Commun S0006-291X(17):32190–32193. https://doi.org/10.1016/j.bbrc.2017.11.013

    Article  CAS  Google Scholar 

  44. Shi G, Shi J, Liu K, Liu N, Wang Y, Fu Z, Ding J, Jia L et al (2013) Increased miR-195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury. Glia 61(4):504–512. https://doi.org/10.1002/glia.22451

    Article  PubMed  Google Scholar 

  45. Xia L, Zhang Y, Dong T (2016) Inhibition of microRNA-221 alleviates neuropathic pain through targeting suppressor of cytokine signaling 1. J Mol Neurosci 59(3):411–420. https://doi.org/10.1007/s12031-016-0748-1

    Article  CAS  PubMed  Google Scholar 

  46. Liu S, Zhu B, Sun Y, Xie X (2015) miR-155 modulates the progression of neuropathic pain through targeting SGK3. Int J Clin Exp Pathol 8(11):14374–14382

    PubMed  PubMed Central  Google Scholar 

  47. Tan Y, Yang J, Xiang K, Tan Q, Guo Q (2015) Suppression of microRNA-155 attenuates neuropathic pain by regulating SOCS1 signalling pathway. Neurochem Res 40(3):550–560. https://doi.org/10.1007/s11064-014-1500-2

    Article  CAS  PubMed  Google Scholar 

  48. Yan XT, Zhao Y, Cheng XL, He XH, Wang Y, Zheng WZ, Chen H, Wang YL (2018) Inhibition of miR-200b/miR-429 contributes to neuropathic pain development through targeting zinc finger E box binding protein-1. J Cell Physiol 233(6):4815–4824. https://doi.org/10.1002/jcp.26284

    Article  CAS  PubMed  Google Scholar 

  49. Xu L, Wang Q, Jiang W, Yu S, Zhang S (2019) MiR-34c ameliorates neuropathic pain by targeting NLRP3 in a mouse model of chronic constriction injury. Neuroscience 399:125–134. https://doi.org/10.1016/j.neuroscience.2018.12.030

    Article  CAS  PubMed  Google Scholar 

  50. Ji LJ, Shi J, Lu JM, Huang QM (2018) MiR-150 alleviates neuropathic pain via inhibiting toll-like receptor 5. J Cell Biochem 119(1):1017–1026. https://doi.org/10.1002/jcb.26269

    Article  CAS  PubMed  Google Scholar 

  51. Zhang Y, Su Z, Liu HL, Li L, Wei M, Ge DJ, Zhang ZJ (2018) Effects of miR-26a-5p on neuropathic pain development by targeting MAPK6 in in CCI rat models. Biomed Pharmacother 107:644–649. https://doi.org/10.1016/j.biopha.2018.08.005

    Article  CAS  PubMed  Google Scholar 

  52. Shen F, Zheng H, Zhou L, Li W, Zhang Y, Xu X (2019) LINC00657 expedites neuropathic pain development by modulating miR-136/ZEB1 axis in a rat model. J Cell Biochem 120(1):1000–1010. https://doi.org/10.1002/jcb.27466

    Article  CAS  PubMed  Google Scholar 

  53. Gao L, Pu X, Huang Y, Huang J (2019) MicroRNA-340-5p relieved chronic constriction injury-induced neuropathic pain by targeting Rap1A in rat model. Genes Genomics 41(6):713–721. https://doi.org/10.1007/s13258-019-00802-0

    Article  CAS  PubMed  Google Scholar 

  54. Cai L, Liu X, Guo Q, Huang Q, Zhang Q, Cao Z (2019) MiR-15a attenuates peripheral nerve injury-induced neuropathic pain by targeting AKT3 to regulate autophagy. Genes Genomics 42:77–85. https://doi.org/10.1007/s13258-019-00881-z

    Article  CAS  PubMed  Google Scholar 

  55. Xie T, Zhang J, Kang Z, Liu F, Lin Z (2019) miR-101 down-regulates mTOR expression and attenuates neuropathic pain in chronic constriction injury rat models. Neurosci Res. https://doi.org/10.1016/j.neures.2019.09.002

  56. Zhang Y, Liu HL, An LJ, Li L, Wei M, Ge DJ, Su Z (2019) miR-124-3p attenuates neuropathic pain induced by chronic sciatic nerve injury in rats via targeting EZH2. J Cell Biochem 120(4):5747–5755. https://doi.org/10.1002/jcb.27861

    Article  CAS  PubMed  Google Scholar 

  57. Tian J, Song T, Wang W, Wang H, Zhang Z (2019) miR-129-5p Alleviates neuropathic pain through regulating HMGB1 expression in CCI rat models. J Mol Neurosci 70:84–93. https://doi.org/10.1007/s12031-019-01403-y

    Article  CAS  PubMed  Google Scholar 

  58. Ji LJ, Su J, Xu AL, Pang B, Huang QM (2018) MiR-134-5p attenuates neuropathic pain progression through targeting Twist1. J Cell Biochem 120:1694–1701. https://doi.org/10.1002/jcb.27486

    Article  CAS  Google Scholar 

  59. You H, Zhang L, Chen Z, Liu W, Wang H, He H (2019) MiR-20b-5p relieves neuropathic pain by targeting Akt3 in a chronic constriction injury rat model. Synapse 73(12). https://doi.org/10.1002/syn.22125

  60. Zhong L, Fu K, Xiao W, Wang F, Shen LL (2018) Overexpression of miR-98 attenuates neuropathic pain development via targeting STAT3 in CCI rat models. J Cell Biochem 120:7989–7997. https://doi.org/10.1002/jcb.28076

    Article  CAS  Google Scholar 

  61. Yu Y, Zhu M, Zhao Y, Xu M, Qiu M (2018) Overexpression of TUSC7 inhibits the inflammation caused by microglia activation via regulating miR-449a/PPAR-gamma. Biochem Biophys Res Commun 503(2):1020–1026. https://doi.org/10.1016/j.bbrc.2018.06.111

    Article  CAS  PubMed  Google Scholar 

  62. Huang L, Wang L (2019) Upregulation of miR-183 represses neuropathic pain through inhibiton of MAP3K4 in CCI rat models. J Cell Physiol 235:3815–3822. https://doi.org/10.1002/jcp.29276

    Article  CAS  PubMed  Google Scholar 

  63. Dragomir MP, Knutsen E, Calin GA (2018) SnapShot: unconventional miRNA functions. Cell 174(4):1038–1038 e1031. https://doi.org/10.1016/j.cell.2018.07.040

    Article  CAS  PubMed  Google Scholar 

  64. Svahn AJ, Giacomotto J, Graeber MB, Rinkwitz S, Becker TS (2016) miR-124 contributes to the functional maturity of microglia. Dev Neurobiol 76(5):507–518. https://doi.org/10.1002/dneu.22328

    Article  CAS  PubMed  Google Scholar 

  65. Ponomarev ED, Veremeyko T, Barteneva N, Krichevsky AM, Weiner HL (2011) MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-alpha-PU.1 pathway. Nat Med 17(1):64–70. https://doi.org/10.1038/nm.2266

    Article  CAS  PubMed  Google Scholar 

  66. Louw AM, Kolar MK, Novikova LN, Kingham PJ, Wiberg M, Kjems J, Novikov LN (2016) Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury. Nanomedicine 12(3):643–653. https://doi.org/10.1016/j.nano.2015.10.011

    Article  CAS  PubMed  Google Scholar 

  67. Conrad AT, Dittel BN (2011) Taming of macrophage and microglial cell activation by microRNA-124. Cell Res 21(2):213–216. https://doi.org/10.1038/cr.2011.9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Grace PM, Strand KA, Galer EL, Maier SF, Watkins LR (2018) MicroRNA-124 and microRNA-146a both attenuate persistent neuropathic pain induced by morphine in male rats. Brain Res 1692:9–11. https://doi.org/10.1016/j.brainres.2018.04.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Willemen HL, Huo X-J, Mao-Ying Q-L, Zijlstra J, Heijnen CJ, Kavelaars A (2012) MicroRNA-124 as a novel treatment for persistent hyperalgesia. J Neuroinflammation 9:143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Qiu S, Feng Y, LeSage G, Zhang Y, Stuart C, He L, Li Y, Caudle Y et al (2015) Chronic morphine-induced microRNA-124 promotes microglial immunosuppression by modulating P65 and TRAF6. J Immunol 194(3):1021–1030. https://doi.org/10.4049/jimmunol.1400106

    Article  CAS  PubMed  Google Scholar 

  71. Veremeyko T, Kuznetsova IS, Dukhinova M, A WYY, Kopeikina E, Barteneva NS, Ponomarev ED (2019) Neuronal extracellular microRNAs miR-124 and miR-9 mediate cell-cell communication between neurons and microglia. J Neurosci Res 97(2):162–184. https://doi.org/10.1002/jnr.24344

    Article  CAS  PubMed  Google Scholar 

  72. Zheng X, Huang H, Liu J, Li M, Liu M, Luo T (2018) Propofol attenuates inflammatory response in LPS-activated microglia by regulating the miR-155/SOCS1 pathway. Inflammation 41(1):11–19. https://doi.org/10.1007/s10753-017-0658-6

    Article  CAS  PubMed  Google Scholar 

  73. Cardoso AL, Guedes JR, Pereira de Almeida L, Pedroso de Lima MC (2012) miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production. Immunology 135(1):73–88. https://doi.org/10.1111/j.1365-2567.2011.03514.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kallenborn-Gerhardt W, Hohmann SW, Syhr KM, Schroder K, Sisignano M, Weigert A, Lorenz JE, Lu R et al (2014) Nox2-dependent signaling between macrophages and sensory neurons contributes to neuropathic pain hypersensitivity. Pain 155(10):2161–2170. https://doi.org/10.1016/j.pain.2014.08.013

    Article  CAS  PubMed  Google Scholar 

  75. Kim D, You B, Jo EK, Han SK, Simon MI, Lee SJ (2010) NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain. Proc Natl Acad Sci U S A 107(33):14851–14856. https://doi.org/10.1073/pnas.1009926107

    Article  PubMed  PubMed Central  Google Scholar 

  76. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40(2):140–155. https://doi.org/10.1002/glia.10161

    Article  PubMed  Google Scholar 

  77. Yang Z, Xu J, Zhu R, Liu L (2017) Down-regulation of miRNA-128 contributes to neuropathic pain following spinal cord injury via activation of P38. Med Sci Monit 23:405–411. https://doi.org/10.12659/msm.898788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Majer O, Liu B, Barton GM (2017) Nucleic acid-sensing TLRs: trafficking and regulation. Curr Opin Immunol 44:26–33. https://doi.org/10.1016/j.coi.2016.10.003

    Article  CAS  PubMed  Google Scholar 

  79. Beutler ALBB (2010) Intracellular Toll-like receptors. Immunity 32:305–315

    Article  PubMed  Google Scholar 

  80. Zhang L, Li YJ, Wu XY, Hong Z, Wei WS (2015) MicroRNA-181c negatively regulates the inflammatory response in oxygen-glucose-deprived microglia by targeting Toll-like receptor 4. J Neurochem 132(6):713–723. https://doi.org/10.1111/jnc.13021

    Article  CAS  PubMed  Google Scholar 

  81. Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, Ji RR (2014) Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 82(1):47–54. https://doi.org/10.1016/j.neuron.2014.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429(3):403–417. https://doi.org/10.1042/BJ20100323

    Article  CAS  PubMed  Google Scholar 

  83. Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA (2009) p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol Med 15(8):369–379. https://doi.org/10.1016/j.molmed.2009.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Clark AK, D'Aquisto F, Gentry C, Marchand F, McMahon SB, Malcangio M (2006) Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. J Neurochem 99(3):868–880. https://doi.org/10.1111/j.1471-4159.2006.04126.x

    Article  CAS  PubMed  Google Scholar 

  85. Svensson CI, Fitzsimmons B, Azizi S, Powell HC, Hua XY, Yaksh TL (2005) Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J Neurochem 92(6):1508–1520. https://doi.org/10.1111/j.1471-4159.2004.02996.x

    Article  CAS  PubMed  Google Scholar 

  86. Ji RR, Suter MR (2007) p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain 3:33. https://doi.org/10.1186/1744-8069-3-33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lin X, Wang M, Zhang J, Xu R (2014) p38 MAPK: a potential target of chronic pain. Curr Med Chem 21(38):4405–4418. https://doi.org/10.2174/0929867321666140915143040

    Article  CAS  PubMed  Google Scholar 

  88. Jadhav SP, Kamath SP, Choolani M, Lu J, Dheen ST (2014) MicroRNA-200b modulates microglia-mediated neuroinflammation via the cJun/MAPK pathway. J Neurochem 130(3):388–401. https://doi.org/10.1111/jnc.12731

    Article  CAS  PubMed  Google Scholar 

  89. Chen W (2016) MicroRNA-16 alleviates inflammatory pain by targeting Ras-related protein 23 (RAB23) and inhibiting p38 MAPK activation. Med Sci Monit 22:3894–3901. https://doi.org/10.12659/MSM.897580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fu X, Shen Y, Wang W, Li X (2018) MiR-30a-5p ameliorates spinal cord injury-induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling. Clin Exp Pharmacol Physiol 45(1):68–74. https://doi.org/10.1111/1440-1681.12856

    Article  CAS  PubMed  Google Scholar 

  91. Inoue K (2006) The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 109(1–2):210–226. https://doi.org/10.1016/j.pharmthera.2005.07.001

    Article  CAS  PubMed  Google Scholar 

  92. Tsuda M, Inoue K (2016) Neuron–microglia interaction by purinergic signaling in neuropathic pain following neurodegeneration. Neuropharmacology 104:76–81. https://doi.org/10.1016/j.neuropharm.2015.08.042

    Article  CAS  PubMed  Google Scholar 

  93. Inoue K, Tsuda M (2012) Purinergic systems, neuropathic pain and the role of microglia. Exp Neurol 234(2):293–301. https://doi.org/10.1016/j.expneurol.2011.09.016

    Article  CAS  PubMed  Google Scholar 

  94. Ferrari D, Bianchi N, Eltzschig HK, Gambari R (2016) MicroRNAs modulate the purinergic signaling network. Trends Mol Med 22(10):905–918. https://doi.org/10.1016/j.molmed.2016.08.006

    Article  CAS  PubMed  Google Scholar 

  95. Zabala A, Vazquez-Villoldo N, Rissiek B, Gejo J, Martin A, Palomino A, Perez-Samartin A, Pulagam KR et al (2018) P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. EMBO Mol Med 10(8):1–20. https://doi.org/10.15252/emmm.201708743

    Article  CAS  Google Scholar 

  96. Beggs S, Trang T, Salter MW (2012) P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15(8):1068–1073. https://doi.org/10.1038/nn.3155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K (2011) Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model. Neurosci Lett 504(1):57–61. https://doi.org/10.1016/j.neulet.2011.08.058

    Article  CAS  PubMed  Google Scholar 

  98. Parisi C, Napoli G, Pelegrin P, Volonte C (2016) M1 and M2 functional imprinting of primary microglia: role of P2X7 activation and miR-125b. Mediat Inflamm 2016:2989548–2989549. https://doi.org/10.1155/2016/2989548

    Article  CAS  Google Scholar 

  99. Kynast KL, Russe OQ, Geisslinger G, Niederberger E (2013) Novel findings in pain processing pathways: implications for miRNAs as future therapeutic targets. Expert Rev Neurother 13(5):515–525. https://doi.org/10.1586/ern.13.34

    Article  CAS  PubMed  Google Scholar 

  100. Kress M, Huttenhofer A, Landry M, Kuner R, Favereaux A, Greenberg D, Bednarik J, Heppenstall P et al (2013) MicroRNAs in nociceptive circuits as predictors of future clinical applications. Front Mol Neurosci 6:33. https://doi.org/10.3389/fnmol.2013.00033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29(43):13435–13444. https://doi.org/10.1523/JNEUROSCI.3257-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chen YJ, Zhu H, Zhang N, Shen L, Wang R, Zhou JS, Hu JG, Lu HZ (2015) Temporal kinetics of macrophage polarization in the injured rat spinal cord. J Neurosci Res 93(10):1526–1533. https://doi.org/10.1002/jnr.23612

    Article  CAS  PubMed  Google Scholar 

  103. Crain JM, Nikodemova M, Watters JJ (2013) Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res 91(9):1143–1151. https://doi.org/10.1002/jnr.23242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gawad C, Koh W, Quake SR (2016) Single-cell genome sequencing: current state of the science. Nat Rev Genet 17(3):175–188. https://doi.org/10.1038/nrg.2015.16

    Article  CAS  PubMed  Google Scholar 

  105. Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F et al (2019) Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50(1):253–271 e256. https://doi.org/10.1016/j.immuni.2018.11.004

    Article  CAS  PubMed  Google Scholar 

  106. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173(5):1073–1081. https://doi.org/10.1016/j.cell.2018.05.003

    Article  CAS  PubMed  Google Scholar 

  107. Record M, Carayon K, Poirot M, Silvente-Poirot S (2014) Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta 1841(1):108–120. https://doi.org/10.1016/j.bbalip.2013.10.004

    Article  CAS  PubMed  Google Scholar 

  108. Shah R, Patel T, Freedman JE (2018) Circulating extracellular vesicles in human disease. N Engl J Med 379(22):2180–2181. https://doi.org/10.1056/NEJMc1813170

    Article  PubMed  Google Scholar 

  109. Simeoli R, Montague K, Jones HR, Castaldi L, Chambers D, Kelleher JH, Vacca V, Pitcher T et al (2017) Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat Commun 8(1):1778. https://doi.org/10.1038/s41467-017-01841-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. McDonald MK, Tian Y, Qureshi RA, Gormley M, Ertel A, Gao R, Aradillas Lopez E, Alexander GM et al (2014) Functional significance of macrophage-derived exosomes in inflammation and pain. Pain 155(8):1527–1539. https://doi.org/10.1016/j.pain.2014.04.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ge X, Guo M, Hu T, Li W, Huang S, Yin Z, Li Y, Chen F et al (2020) Increased microglial exosomal miR-124-3p alleviates neurodegeneration and improves cognitive outcome after rmTBI. Mol Ther 28(2):503–522. https://doi.org/10.1016/j.ymthe.2019.11.017

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the grant from the National Natural Science Foundation of China (81870879) and the Natural Science Foundation of Guangdong Province(2017A030313534).

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Jun Zhou conceptualized the review. Simin Tang was a major contributor in writing the manuscript with the help of Huan Jing and Fuhu Song. Haicheng Huang, Wenjun Li, and Guiling Xie drew the figures. All authors read and approved the final manuscript.

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Correspondence to Jun Zhou.

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Tang, S., Jing, H., Song, F. et al. MicroRNAs in the Spinal Microglia Serve Critical Roles in Neuropathic Pain. Mol Neurobiol 58, 132–142 (2021). https://doi.org/10.1007/s12035-020-02102-1

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