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Up-Regulation of CX3CL1 via STAT3 Contributes to SMIR-Induced Chronic Postsurgical Pain

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Abstract

Chronic postsurgical pain (CPSP) often occurs after surgery and has a strong impact on patients’ daily lives. However, the underlying mechanism of CPSP remains unknown. Here, we used a skin/muscle incision and retraction (SMIR) model to investigate the role of CX3CL1 in SMIR-induced pain and its underlying mechanism. We found that up-regulation of CX3CL1 in the spinal dorsal horn contributed to SMIR-induced mechanical allodynia. The use of a CX3CL1-neutralizing antibody to block CX3CL1 attenuated mechanical allodynia induced by SMIR surgery. We also found that phospho-STAT3 co-localizes with CX3CL1 in spinal neurons after SMIR surgery and that this contributes to SMIR-induced mechanical allodynia. Intrathecal administration of the STAT3 inhibitor S3I-201 suppressed up-regulation of CX3CL1 at both the protein and mRNA levels after SMIR surgery. Chromatin immunoprecipitation further demonstrated that SMIR promotes the recruitment of STAT3 to the cx3cl1 gene promoter (− 1032/− 1022). These findings suggest that activation of STAT3 after SMIR mediates the up-regulation of CX3CL1, leading to mechanical allodynia, and that this upregulation may partly be due to the enhanced recruitment of STAT3 to the cx3cl1 gene promoter after SMIR.

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References

  1. Macrae WA (2008) Chronic post-surgical pain: 10 years on. Br J Anaesth 101:77–86

    CAS  PubMed  Google Scholar 

  2. Searle R, Simpson K (2010) Chronic post-surgical pain. Curr Opin Anaesthesiol 25:584

    Google Scholar 

  3. Kehlet H, Jensen TS, Woolf CJ (2006) Persistent postsurgical pain: risk factors and prevention. Lancet 367:1618–1625

    PubMed  Google Scholar 

  4. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I (2013) Pharmacotherapy for the prevention of chronic pain after surgery in adults. The Cochrane database of systematic reviews: CD008307

  5. Cregg R, Anwar S, Farquhar-Smith P (2013) Persistent postsurgical pain. Curr Opin Support Palliat Care 7:144–152

    PubMed  Google Scholar 

  6. Flatters SJ (2008) Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR). Pain 135:119–130

    PubMed  Google Scholar 

  7. Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385:640–644

    CAS  PubMed  Google Scholar 

  8. Lindia JA, Mcgowan E, Jochnowitz N, Abbadie C (2005) Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. J Pain 6:434–438

    CAS  PubMed  Google Scholar 

  9. Li D, Huang ZZ, Ling YZ, Wei JY, Cui Y, Zhang XZ, Zhu HQ, Xin WJ (2015) Up-regulation of CX3CL1 via nuclear factor-κB-dependent histone acetylation is involved in paclitaxel-induced peripheral neuropathy. Anesthesiology 122:1142–1151

    CAS  PubMed  Google Scholar 

  10. Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC (2004) Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 20:1150–1160

    PubMed  Google Scholar 

  11. Recio G (2009) Expression of CX3CL1/CX3CR1 and neuropathic pain in a lumbar disc herniation rat model. Spine J 9:14S

    Google Scholar 

  12. Milligan E, Zapata V, Schoeniger D, Chacur M, Green P, Poole S, Martin D, Maier SF, Watkins LR (2005) An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur J Neurosci 22:2775–2782

    CAS  PubMed  Google Scholar 

  13. Zhang ZJ, Jiang BC, Gao YJ (2017) Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain. Cell Mol Life Sci 1–17

  14. Liou JT, Lee CM, Day YJ (2013) The immune aspect in neuropathic pain: role of chemokines. Acta Anaesthesiol Taiwan 51:127–132

    PubMed  Google Scholar 

  15. Liu W, Jiang L, Bian C, Liang Y, Xing R, Yishakea M, Dong J (2016) Role of CX3CL1 in diseases. Arch Immunol Ther Exp 64:371–383

    Google Scholar 

  16. Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR (2007) Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav Immun 21:642–651

    CAS  PubMed  Google Scholar 

  17. Xue ZJ, Shen L, Wang ZY, Hui SY, Huang YG, Ma C (2014) STAT3 inhibitor WP1066 as a novel therapeutic agent for bCCI neuropathic pain rats. Brain Res 1583:79–88

    CAS  PubMed  Google Scholar 

  18. Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozakisaitoh H, Koyanagi S, Ohdo S, Ji RR, Salter MW (2011) JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain 134:1127–1139

    PubMed  PubMed Central  Google Scholar 

  19. Dominguez E, Rivat C, Pommier B, Mauborgne A, Pohl M (2008) JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat. J Neurochem 107:50–60

    CAS  PubMed  Google Scholar 

  20. Bromberg J (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473

    CAS  PubMed  Google Scholar 

  21. Liu X, Tian Y, Lu N, Gin T, Cheng CH, Chan MT (2013) Stat3 inhibition attenuates mechanical allodynia through transcriptional regulation of chemokine expression in spinal astrocytes. PLoS ONE 8:e75804

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    CAS  PubMed  Google Scholar 

  23. Lopachin RM, Rudy TA, Yaksh TL (1981) An improved method for chronic catheterization of the rat spinal subarachnoid space. Physiol Behav 27:559–561

    CAS  PubMed  Google Scholar 

  24. Liu C, Luan S, Ouyang H, Huang Z, Wu S, Ma C, Wei J, Xin W (2015) Upregulation of CCL2 via ATF3/c-Jun interaction mediated the Bortezomib-induced peripheral neuropathy. Brain Behav Immun 53:96–104

    PubMed  Google Scholar 

  25. Chen H, Jiang YS, Sun Y, Xiong YC (2015) p38 and/or interleukin-1 beta pathway via toll-like receptor 4 contributed to the skin and/or muscle incision and retraction-induced allodynia. J Surg Res 197:339–347

    CAS  PubMed  Google Scholar 

  26. Bai L, Wang X, Li Z, Kong C, Zhao Y, Qian JL, Kan Q, Zhang W, Xu JT (2016) Upregulation of chemokine CXCL12 in the dorsal root ganglia and spinal cord contributes to the development and maintenance of neuropathic pain following spared nerve injury in rats. Neurosci Bull 32:1–14

    Google Scholar 

  27. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dominguez E, Mauborgne A, Mallet J, Desclaux M, Pohl M (2010) SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury. J Neurosci 30:5754–5766

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang HT, Liu W, Luo AL, Ma C, Huang YG (2012) Prevalence and risk factors of chronic post-thoracotomy pain in Chinese patients from Peking Union Medical College Hospital. Natl Med J China 125:3033–3038

    Google Scholar 

  30. White FA, Bhangoo SK, Miller RJ (2005) Chemokines: integrators of pain and inflammation. Nat Rev Drug Discovery 4:834–844

    CAS  PubMed  Google Scholar 

  31. Carreira EU, Carregaro V, Teixeira MM, Moriconi A, Aramini A, Jr WAV, Ferreira SH, Cunha FQ, Cunha TM (2013) Neutrophils recruited by CXCR1/2 signalling mediate post-incisional pain. Eur J Pain 17:654–663

    CAS  PubMed  Google Scholar 

  32. Peters CM, Eisenach JC (2010) Contribution of the chemokine CCL2 to mechanical hypersensitivity following surgical incision in rats. Anesthesiology 112:1250–1258

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Souza GR, Talbot J, Lotufo CM, Cunha FQ, Cunha TM, Ferreira SH (2013) Fractalkine mediates inflammatory pain through activation of satellite glial cells. Proc Natl Acad Sci USA 110:11193–11198

    CAS  PubMed  Google Scholar 

  34. Hains BC, Waxman SG (2006) Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci 26:4308–4317

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Inoue K, Tsuda M (2013) Microglia and neuropathic pain. Glia 12:768–772

    Google Scholar 

  36. Ji RR, Berta T, Nedergaard M (2013) Glia and pain: is chronic pain a gliopathy? Pain® 154:S10–S28

    Google Scholar 

  37. Ying YL, Wei XH, Xu XB, She SZ, Zhou LJ, Lv J, Li D, Zheng B, Liu XG (2014) Over-expression of P2 × 7 receptors in spinal glial cells contributes to the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR) in rats. Exp Neurol 261:836–843

    CAS  PubMed  Google Scholar 

  38. Clark AK, Malcangio M (2014) Fractalkine/CX3CR1 signaling during neuropathic pain. Front Cell Neurosci 8:121

    PubMed  PubMed Central  Google Scholar 

  39. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D (2015) Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 18:1081–1083

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mapplebeck JC, Beggs S, Salter MW (2016) Sex differences in pain: a tale of two immune cells. Pain 157(Suppl 1):S2–S6

    PubMed  Google Scholar 

  41. Buschdienstfertig M (2013) IL-4, JAK-STAT signaling, and pain. JAK-STAT 2:e27638

    Google Scholar 

  42. Nicolas CS, Amici M, Bortolotto ZA, Doherty A, Csaba Z, Fafouri A, Dournaud P, Gressens P, Collingridge GL, Peineau S (2013) The role of JAK-STAT signaling within the CNS. JAK-STAT 2:e22925

    PubMed  PubMed Central  Google Scholar 

  43. Raible DJ, Frey LC, Del Angel YC, Carlsen J, Hund D, Russek SJ, Smith B, Brooks-Kayal AR (2015) JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI. Exp Neurol 271:445–456

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Xu T, Zhang XL, Ouyang HD, Li ZY, Liu CC, Huang ZZ, Xu J, Wei JY, Nie BL, Ma C (2017) Epigenetic upregulation of CXCL12 expression mediates anti-tubulin chemotherapeutics-induced neuropathic pain. Pain 158:637–648

    CAS  PubMed  Google Scholar 

  45. Ernst MB, Wunderlich CM, Hess S, Paehler M, Mesaros A, Koralov SB, Kleinridders A, Husch A, Münzberg H, Hampel B (2009) Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. J Neurosci 29:11582–11593

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Reich NC, Liu L (2006) Tracking STAT nuclear traffic. Nat Rev Immunol 6:602–612

    CAS  PubMed  Google Scholar 

  47. Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12:11–19

    CAS  PubMed  Google Scholar 

  48. Hazanhalevy I, Harris D, Liu Z, Liu J, Li P, Chen X, Shanker S, Ferrajoli A, Keating MJ, Estrov Z (2010) STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood 115:2852–2863

    CAS  Google Scholar 

  49. Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, Dang Y, Chu Y, Fan J, He R (2016) FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Can Res 76:4124–4135

    CAS  Google Scholar 

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (81600955), the Natural Science Foundation of Shanghai (17ZR1438200), the 1255 Discipline Construction Program Foundation of the First Affiliated Hospital of SMMU (125532200) and the Research Projects of Shanghai Municipal Commission of Health and Family Planning (201440364).

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  1. Yijia Shen, Dai Li, and Bo Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital of the Second Military Medical University, 168 Changhai Road, Shanghai, 200433, People’s Republic of China

    Yijia Shen, Dai Li, Bo Li, Peng Xi, Yun Zhang, Youshui Jiang, Yehao Xu, Hui Chen & Yuanchang Xiong

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  1. Yijia Shen
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Correspondence to Hui Chen or Yuanchang Xiong.

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Shen, Y., Li, D., Li, B. et al. Up-Regulation of CX3CL1 via STAT3 Contributes to SMIR-Induced Chronic Postsurgical Pain. Neurochem Res 43, 556–565 (2018). https://doi.org/10.1007/s11064-017-2449-8

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  • DOI: https://doi.org/10.1007/s11064-017-2449-8

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