Advertisement

Neurochemical Research

, Volume 43, Issue 8, pp 1631–1640 | Cite as

E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury

  • Pengfei Xue
  • Xiaojuan Liu
  • Yiming Shen
  • Yuanyuan Ju
  • Xiongsong Lu
  • Jinlong Zhang
  • Guanhua Xu
  • Yuyu Sun
  • Jiajia Chen
  • Haiyan Gu
  • Zhiming Cui
  • Guofeng Bao
Original Paper
  • 67 Downloads

Abstract

E3 ubiquitin ligase c-Caritas B cell lymphoma (c-cbl) is associated with negative regulation of receptor tyrosine kinases, signal transduction of antigens and cytokine receptors, and immune response. However, the expression and function of c-cbl in the regulation of neuropathic pain after chronic constriction injury (CCI) are unknown. In rat CCI model, c-cbl inhibited the activation of spinal cord microglia and the release of pro-inflammatory factors including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), which alleviated mechanical and heat pain through down-regulating extracellular signal-regulated kinase (ERK) pathway. Additionally, exogenous TNF-α inhibited c-cbl protein level vice versa. In the primary microglia transfected with c-cbl siRNA, when treated with TNF-α or TNF-α inhibitor, the corresponding secretion of IL-1β and IL-6 did not change. In summary, CCI down-regulated c-cbl expression and induced the activation of microglia, then activated microglia released inflammatory factors via ERK signaling to cause pain. Our data might supply a novel molecular target for the therapy of CCI-induced neuropathic pain.

Keywords

c-Caritas B cell lymphoma (c-cbl) Microglia Inflammatory factors Extracellular signal-regulated kinase (ERK) Chronic constriction injury (CCI) 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81501076, 81401365), the Science and Technology of construction and people’s livelihood Foundation of Jiangsu Province (BL2014061), Jiangsu Province Young Medical Key Talents Project of China (QNRC2016407), the Nantong Science and Technology Innovation Project (No. MS12015056); and the 14th Six Talents Peak Project of Jiangsu Province (No. SWYY-058), and National Natural Youth Science Fund (No. 81702216).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Gosselin RD, Suter MR, Ji RR, Decosterd I (2010) Glial cells and chronic pain. Neuroscientist 16:519CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Zhang ZJ, Jiang BC, Gao YJ (2017) Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain. Cell Mol Life Sci 74:1–17CrossRefGoogle Scholar
  3. 3.
    Carballovillalobos AI, Gonzáleztrujano ME, Alvaradovázquez N, Lópezmuñoz FJ (2017) Pro-inflammatory cytokines involvement in the hesperidin antihyperalgesic effects at peripheral and central levels in a neuropathic pain model. Inflammopharmacology 25:1–5CrossRefGoogle Scholar
  4. 4.
    Zuo W, Huang F, Chiang YJ, Li M, Du J, Ding Y, Zhang T, Lee H, Jeong L, Chen Y (2013) c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor. Mol Cell 49:499CrossRefPubMedGoogle Scholar
  5. 5.
    Caligiuri MA, Briesewitz R, Yu J, Wang L, Wei M, Arnoczky KJ, Marburger TB, Wen J, Perrotti D, Bloomfield CD (2007) Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood 110:1022–1024CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mohapatra B, Ahmad G, Nadeau S, Zutshi N, An W, Scheffe S, Dong L, Feng D, Goetz B, Arya P, Bailey TA, Palermo N, Borgstahl GE, Natarajan A, Raja SM, Naramura M, Band V, Band H (2013) Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases. Biochim Biophys Acta 1833:122–139CrossRefPubMedGoogle Scholar
  7. 7.
    Bachmaier K, Krawczyk C (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403:211–216CrossRefPubMedGoogle Scholar
  8. 8.
    Husnjak K, Dikic I (2012) Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem 81:291–322CrossRefPubMedGoogle Scholar
  9. 9.
    Qiao G, Zhao Y, Li Z, Tang PQ, Langdon WY, Yang T, Zhang J (2013) T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells. J Immunol 191:632–639CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wallner S, Lutz-Nicoladoni C, Tripp CH, Gastl G, Baier G, Penninger JM, Stoitzner P, Wolf D (2013) The role of the e3 ligase cbl-B in murine dendritic cells. PLoS ONE 8:e65178CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dong L, Li YZ, An HT, Wang YL, Chen SH, Qian YJ, Wang K, Zhen JL, Fan Z, Gong XL (2016) The E3 ubiquitin ligase c-Cbl inhibits microglia-mediated CNS inflammation by regulating PI3K/Akt/NF-κB pathway. CNS Neurosci Ther 22:661CrossRefPubMedGoogle Scholar
  12. 12.
    Schafer Dorothy P, Lehrman Emily K, Kautzman Amanda G, Koyama R, Mardinly Alan R, Yamasaki R, Ransohoff Richard M, Greenberg Michael E, Barres Ben A, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B (2015) Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol 36:605–613CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468CrossRefPubMedGoogle Scholar
  15. 15.
    Colton CA, Wilcock DM (2010) Assessing activation states in microglia. CNS Neurol Disord Drug Targets 9:174–191CrossRefPubMedGoogle Scholar
  16. 16.
    Masuda T, Prinz M (2016) Microglia: a unique versatile cell in the central nervous system. ACS Chem Neurosci 7:428–434CrossRefPubMedGoogle Scholar
  17. 17.
    Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61:71–90CrossRefPubMedGoogle Scholar
  18. 18.
    Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110CrossRefPubMedGoogle Scholar
  19. 19.
    Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107CrossRefPubMedGoogle Scholar
  20. 20.
    Hartung JE, Ciszek BP, Nackley AG (2014) beta2- and beta3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines. Pain 155:1346–1355CrossRefPubMedGoogle Scholar
  21. 21.
    Zhu X, Yao L, Guo A, Li A, Sun H, Wang N, Liu H, Duan Z, Cao J (2014) CAP1 was associated with actin and involved in Schwann cell differentiation and motility after sciatic nerve injury. J Mol Histol 45:337–348CrossRefPubMedGoogle Scholar
  22. 22.
    Wallner FK, Hopkins MH, Lindvall T, Olofsson P, Tilevik A (2017) Cytokine correlation analysis based on drug perturbation. Cytokine 90:73–79CrossRefPubMedGoogle Scholar
  23. 23.
    Kong H, Omran A, Ashhab MU, Gan N, Peng J, He F, Wu L, Deng X, Yin F (2014) Changes in microglial inflammation-related and brain-enriched microRNAs expressions in response to in vitro oxygen–glucose deprivation. Neurochem Res 39:233–243CrossRefPubMedGoogle Scholar
  24. 24.
    Gioia R, Trégoat C, Dumas PY, Lagarde V, Prouzet-Mauléon V, Desplat V, Sirvent A, Praloran V, Lippert E, Villacreces A (2015) CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia. J Pathol 237:14–24CrossRefPubMedGoogle Scholar
  25. 25.
    Sirvent A, Leroy C, Simon A, Roche V S (2008) The Src-like adaptor protein regulates PDGF-induced actin dorsal ruffles in a c-Cbl-dependent manner. Oncogene 27:3494CrossRefPubMedGoogle Scholar
  26. 26.
    Li H, Li T, Fan J, Fan L, Wang S, Weng X, Han Q, Zhao RC (2015) miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway. Cell Death Differ 22:1935–1945CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kline CL, Olson TL, Irby RB (2009) Src activity alters alpha3 integrin expression in colon tumor cells. Clin Exp Metastasis 26:77CrossRefPubMedGoogle Scholar
  28. 28.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756CrossRefPubMedGoogle Scholar
  29. 29.
    Schäfers M, Svensson CI, Sommer C, Sorkin LS (2003) Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23:2517–2521CrossRefPubMedGoogle Scholar
  30. 30.
    Sommer C, Schäfers M, Marziniak M, Toyka KV (2001) Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 6:67CrossRefPubMedGoogle Scholar
  31. 31.
    Xu JT, Xin WJ, Zang Y, Wu CY, Liu XG (2006) The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. Pain 123:306–321CrossRefPubMedGoogle Scholar
  32. 32.
    Constantin CE, Mair N, Sailer CA, Andratsch M, Xu ZZ, Blumer MJ, Scherbakov N, Davis JB, Bluethmann H, Ji RR, Kress M (2008) Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J Neurosci 28:5072–5081CrossRefPubMedGoogle Scholar
  33. 33.
    Pelletier C, Varin-Blank N, Rivera J, Iannascoli B, Marchand F, David B, Weyer A, Blank U Pelletier C et al (1998) FcRI-mediated induction of TNF- gene expression in the RBL-2H3 mast cell line: regulation by a novel NF-B-like nuclear binding complex. J Immunol 161:4768–4776PubMedGoogle Scholar
  34. 34.
    Ping D, Boekhoudt G, Zhang F, Morris A, Philipsen S, Warren ST, Boss JM (2000) Sp1 binding is critical for promoter assembly and activation of the MCP-1 gene by tumor necrosis factor. J Biol Chem 275:1708CrossRefPubMedGoogle Scholar
  35. 35.
    You M, Flick LM, Yu D, Feng GS (2001) Modulation of the nuclear factor kappa B pathway by Shp-2 tyrosine phosphatase in mediating the induction of interleukin (IL)-6 by IL-1 or tumor necrosis factor. J Exp Med 193:101–110CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Costa B, Trovato AE, Colleoni M, Giagnoni G, Zarini E, Croci T (2005) Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve. Pain 116:52–61CrossRefPubMedGoogle Scholar
  37. 37.
    Komirishetty P, Areti A, Sistla R, Kumar A (2016) Morin mitigates chronic constriction injury (CCI)-induced peripheral neuropathy by inhibiting oxidative stress induced PARP over-activation and neuroinflammation. Neurochem Res 41:2029–2042CrossRefPubMedGoogle Scholar
  38. 38.
    Gabay E, Tal M (2004) Pain behavior and nerve electrophysiology in the CCI model of neuropathic pain. Pain 110:354–360CrossRefPubMedGoogle Scholar
  39. 39.
    Tatsumi E, Yamanaka H, Kobayashi K, Yagi H, Sakagami M, Noguchi K (2015) RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain. Glia 63:216–228CrossRefPubMedGoogle Scholar
  40. 40.
    Echeverry S, Shi XQ, Yang M, Huang H, Wu Y, Lorenzo LE, Perez-Sanchez J, Bonin RP, De Koninck Y, Zhang J (2017) Spinal microglia are required for long-term maintenance of neuropathic pain. Pain 158:1792–1801CrossRefPubMedGoogle Scholar
  41. 41.
    Martini AC, Berta T, Forner S, Chen G, Bento AF, Ji RR, Rae GA (2016) Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection. J Neuroinflammation 13:75CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Liu X, Zhang Z, Cheng Z, Zhang J, Xu S, Liu H, Jia H, Jin Y (2016) Spinal heme oxygenase-1 (HO-1) exerts antinociceptive effects against neuropathic pain in a mouse model of L5 spinal nerve ligation. Pain Med 17:220–229PubMedGoogle Scholar
  43. 43.
    Wang D, Xue Y, Chen Y, Ruan L, Hong Y (2016) Mas-related gene (Mrg) C receptors inhibit mechanical allodynia and spinal microglia activation in the early phase of neuropathic pain in rats. Neurosci Lett 618:115–121CrossRefPubMedGoogle Scholar
  44. 44.
    Zhang T, Sun K, Shen W, Qi L, Yin W, Wang LW (2016) SOCS1 regulates neuropathic pain by inhibiting neuronal sensitization and glial activation in mouse spinal cord. Brain Res Bull 124:231–237CrossRefPubMedGoogle Scholar
  45. 45.
    Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72:3666–3670CrossRefPubMedGoogle Scholar
  46. 46.
    Shubayev VI, Myers RR (2001) Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors. J Neuroimmunol 114:48–56CrossRefPubMedGoogle Scholar
  47. 47.
    Zhang H, Zhang H, Dougherty PM (2013) Dynamic effects of TNF-alpha on synaptic transmission in mice over time following sciatic nerve chronic constriction injury. J Neurophysiol 110:1663–1671CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Jancalek R, Dubovy P, Svizenska I, Klusakova I (2010) Bilateral changes of TNF-alpha and IL-10 protein in the lumbar and cervical dorsal root ganglia following a unilateral chronic constriction injury of the sciatic nerve. J Neuroinflammation 7:11CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Li YY, Wei XH, Lu ZH, Chen JS, Huang QD, Gong QJ (2013) Src/p38 MAPK pathway in spinal microglia is involved in mechanical allodynia induced by peri-sciatic administration of recombinant rat TNF-alpha. Brain Res Bull 96:54–61CrossRefPubMedGoogle Scholar
  50. 50.
    Liu YL, Zhou LJ, Hu NW, Xu JT, Wu CY, Zhang T, Li YY, Liu XG (2007) Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology 52:708–715CrossRefPubMedGoogle Scholar
  51. 51.
    Sommer C, Lindenlaub T, Teuteberg P, Schafers M, Hartung T, Toyka KV (2001) Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res 913:86–89CrossRefPubMedGoogle Scholar
  52. 52.
    Zanella JM, Burright EN, Hildebrand K, Hobot C, Cox M, Christoferson L, McKay WF (2008) Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine (Phila Pa 1976) 33:227–234CrossRefGoogle Scholar
  53. 53.
    Kundu M, Pathak SK (2009) A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis. Nat Immunol 10:918CrossRefPubMedGoogle Scholar
  54. 54.
    Manganaro D, Consonni A, Guidetti GF, Canobbio I, Visconte C, Kim S, Okigaki M, Falasca M, Hirsch E, Kunapuli SP, Torti M (2015) Activation of phosphatidylinositol 3-kinase beta by the platelet collagen receptors integrin alpha2beta1 and GPVI: the role of Pyk2 and c-Cbl. Biochim Biophys Acta 1853:1879–1888CrossRefPubMedGoogle Scholar
  55. 55.
    Dong L, Li YZ, An HT, Wang YL, Chen SH, Qian YJ, Wang K, Zhen JL, Fan Z, Gong XL, Zheng Y, Wang XM (2016) The E3 ubiquitin ligase c-Cbl inhibits microglia-mediated CNS inflammation by regulating PI3K/Akt/NF-kappaB pathway. CNS Neurosci Ther 22:661–669CrossRefPubMedGoogle Scholar
  56. 56.
    Chen SP, Zhou YQ, Liu DQ, Zhang W, Manyande A, Guan XH, Tian YK, Ye DW, Omar DM (2017) PI3K/Akt pathway: a potential therapeutic target for chronic pain. Curr Pharm Des 23:1860–1868CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang L, Fu ZJ, Sun T, Zhao XL, Song WG, Jia MR, Wei GF (2010) [Expression of NF-kappaB and TNF-alpha in spinal dorsal horn in a rat model of neuropathic pain]. Zhonghua Yi Xue Za Zhi 90:1067–1071PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Spine Surgerythe Second Affiliated Hospital of Nantong UniversityNantongChina
  2. 2.Department of Pathogen Biology, Medical CollegeNantong UniversityNantongChina
  3. 3.Department of CardiologyAffiliated Hospital of Nantong UniversityNantongChina
  4. 4.Medical CollegeNantong UniversityNantongChina

Personalised recommendations