Time Course of Peripheral and Central Immune System Alterations in Paclitaxel-Treated Mice: Possible Involvement of Dysfunctional Microglia

Abstract

Despite the importance of microglial cells in chronic pain, the mechanisms of microglial engagement remain controversial. In this study, we examined the changes in immune-related factors in the mesenteric lymph node and spinal cord over time as a treatment regimen for paclitaxel-induced neuropathy (2 mg/kg/day for 5 days). Our data showed that expression of pro- and anti-inflammatory cytokines, Tbx21 (Th1) and Rorc (RORγ; Th17), were increased at 7 days but subsequently normalized after paclitaxel treatment. Monocyte/macrophage functional phenotypes also exhibited a similar pattern in mesenteric lymph node. In the spinal cord, expression of pro- and anti-inflammatory cytokines were decreased at 7 days and recovered at 21 days in paclitaxel-treated mice. Although, mRNA level of TNF-α was transiently increased at 1 day, expression of genes related to microglial homeostatic function (Cx3cr1, Cd200r, TGF-β, IGF-1, and P2ry12) was significantly reduced at 7 and 14 days and restored at 21 days, suggesting the impairment of microglial homeostatic function. In addition, lipofuscin accumulation was increased at 7-14 days and partly normalized at 21 days in the spinal cord. The partly restoration of lipofuscin accumulation at 21 days seems to be related to a reduction in expression of genes involved in cell cycle arrest such as p16 and p21. Collectively, we propose that a process involving dysfunctional microglia, lipofuscin accumulation, and promotion of cell proliferation may explain the onset of paclitaxel-induced neuropathy and recovery after washout.

This is a preview of subscription content, log in to check access.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.

REFERENCES

  1. 1

    Johannes, C.B., Le, T.K., Zhou, X., Johnston, J.A., and Dworkin, R.H., J Pain, 2010, vol. 11, pp. 1230–1239.

    Article  PubMed  Google Scholar 

  2. 2

    Ji, R.R., Xu, Z.Z., and Gao, Y.J., Nat. Rev. Drug Discov. 2014, vol. 13, pp. 533–548.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Kuner, R., Nat. Med., 2010, vol. 16, pp. 1258–1266.

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Chen, G., Zhang, Y.Q., Qadri, Y.J., Serhan, C.N., and Ji, R.R., Neuron, 2018, vol. 100, pp. 1292–1311.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Saijo, K., and Glass, C.K., Nat. Rev. Immunol., 2011, vol. 11, pp. 775–787.

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Noh, M.Y., Lim, S.M., Oh, K.W., Cho, K.A., Park, J., Kim, K.S., Lee, S.J., Kwon, M.S., and Kim, S.H., Stem Cells Transl. Med., 2016, vol. 5, pp. 1538–1549.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Rangaraju, S., Dammer, E.B., Raza, S.A., Rathakrishnan, P., Xiao, H., Gao, T., Duong, D.M., Pennington, M.W., Lah, J.J., Seyfried, N.T., and Levey, A.I., Mol. Neurodegener., 2018, vol. 13, p. 24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ransohoff, R.M., Nat. Neurosci., 2016, vol. 19, pp. 987–991.

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Butovsky, O., and Weiner, H.L., Nat. Rev. Neurosci., 2018, vol. 19, pp. 622–635.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Jaggi, A.S., and Singh, N., Toxicology, 2012, vol. 291, pp. 1–9.

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Li, Y., Zhang, H., Kosturakis, A.K., Jawad, A.B., and Dougherty, P.M., J Pain, 2014, vol. 15, pp. 712–725.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Kawasaki, Y., Zhang, L., Cheng, J.K., and Ji, R.R., J. Neurosci., 2008, vol. 28, pp. 5189–5194.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Grace, P.M., Hutchinson, M.R., Maier, S.F., and Watkins, L.R., Nat. Rev. Immunol., 2014, vol. 14, pp. 217–231.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Liu, C.C., Lu, N., Cui, Y., Yang, T., Zhao, Z.Q., Xin, W.J., and Liu, X.G., Mol. Pain., 2010, vol. 6, p. 76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Zhang, H., Yoon, S.Y., and Dougherty, P.M., J Pain. 2012, vol. 13, pp. 293–303.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Ochi-ishi, R., Nagata, K., Inoue, T., Tozaki-Saitoh, H., Tsuda, M., and Inoue, K., Mol. Pain., 2014, vol. 10, p. 53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Park, H.S., Park, M.J., and Kwon, M.S., Int. Neurourol. J., 2016, vol. 20, pp. S8–S14.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Ha, J.W., You, M.J., Park, H.S., Kim, J.W., and Kwon, M.S., Arch. Pharm. Res., 2019, vol. 42, pp. 359–368.

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Jung, T., Hohn, A., and Grune, T., Methods Mol. Biol. 2010, vol. 594, pp. 173–193.

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Moreno-García, A., Kun, A., Calero, O., Medina, M., and Calero, M., Front. Neurosci., 2018, vol. 12, p. 464.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Warburton, S., Davis, W.E., Southwick, K., Xin, H., Woolley, A.T., Burton, G.F., and Thulin, C.D., Mol. Vis., 2007, vol. 13, pp. 318–329.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Deczkowska, A., Amit, I., and Schwartz, M., Nat. Neurosci. 2018, vol. 21, pp. 779–786.

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Hickman, S., Izzy, S., Sen, P., Morsett, L., and El Khoury, J., Nat. Neurosci., 2018, vol. 21, pp. 1359–1369.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Eijkelkamp, N., Steen-Louws, C., Hartgring, S.A., Willemen, H.L., Prado, J., Lafeber, F.P., Heijnen, C.J., Hack, C.E., van Roon, J.A., and Kavelaars, A., J. Neurosci., 2016, vol. 36, pp. 7353–7363.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Scripture, C.D., Figg, W.D., and Sparreboom, A., Curr. Neuropharmacol., 2006, vol. 4, pp. 165–172.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Staff, N.P., Grisold, A., Grisold, W., and Windebank, A.J., Ann. Neurol., 2017, vol. 81, pp. 772–781.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Childs, B.G., Baker, D.J., Kirkland, J.L., Campisi, J., and van Deursen, J.M., EMBO Rep., 2014, vol. 15, pp. 1139–1153.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Jung, T., Bader, N., and Grune, T., Ann. N. Y. Acad. Sci., 2007, vol. 1119, pp. 97–111.

  29. 29

    Gosselin, D., Link, V.M., Romanoski, C.E., Fonseca, G.J., Eichenfield, D.Z., Spann, N.J., Stender, J.D., Chun, H.B., Garner, H., Geissmann, F., and Glass, C.K., Cell, 2014, vol. 159, pp. 1327–1340.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., Greco, D.J., Smith, S.T., Tweet, G., Humulock, Z., Zrzavy, T., Conde-Sanroman, P., Gacias, M., Weng, Z., Chen, H., Tjon, E., Mazaheri, F., Hartmann, K., Madi, A., Ulrich, J.D., Glatzel, M., Worthmann, A., Heeren, J., Budnik, B., Lemere, C., Ikezu, T., Heppner, F.L., Litvak, V., Holtzman, D.M., Lassmann, H., Weiner, H.L., Ochando, J., Haass, C., and Butovsky, O., Immunity, 2017, vol. 47, pp. 566–581, e569.

  31. 31

    Lund, H., Pieber, M., Parsa, R., Grommisch, D., Ewing, E., Kular, L., Han, J., Zhu, K., Nijssen, J., Hedlund, E., Needhamsen, M., Ruhrmann, S., Guerreiro-Cacais, A.O., Berglund, R., Forteza, M.J., Ketelhuth, D.F.J., Butovsky, O., Jagodic, M., Zhang, X.M., and Harris, R.A., Nat. Immunol., 2018, vol. 19, pp. 1–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Park, M.J., Park, H.S., You, M.J., Yoo, J., Kim, S.H., and Kwon, M.S., Mol. Neurobiol., 2019, vol. 56, pp. 1421–1436.

    CAS  Article  PubMed  Google Scholar 

Download references

Funding

This study was funded by by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (grant number: 2017R1C1B5018178).

Author information

Affiliations

Authors

Contributions

Kim JW has received research grants from NRF; and wrote manuscript. Park HS conducted lipofuscin study and wrote a draft. You MJ conducted immunohistochemistry in the spinal cord. Yang BH and Jang KB conducted qPCR in the lymph node and spinal cord. Kwon MS suggested experimental design and interpreted all data. All authors critically revised the manuscript and approved the final article.

Corresponding author

Correspondence to Min-Soo Kwon.

Ethics declarations

Conflict of interest. The authors declare that they have no conflict of interest.

Ethical approval. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (IACUC approval No. 180009).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jong Wan Kim, Park, H., You, M. et al. Time Course of Peripheral and Central Immune System Alterations in Paclitaxel-Treated Mice: Possible Involvement of Dysfunctional Microglia. Neurochem. J. 14, 204–214 (2020). https://doi.org/10.1134/S1819712420020063

Download citation

Keywords:

  • microglia
  • paclitaxel
  • pain
  • lipofuscin