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

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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.

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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).

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    Authors and Affiliations

    1. Department of Pharmacology, School of Medicine, CHA University, CHA BIO COMPLEX, 335 Pangyo, Bundang-gu, 13488, Seongnam-si, Gyeonggi-do, Republic of Korea

      Jong Wan Kim, Hyun-Sun Park, Min-Jung You, Bohyun Yang, Kyu Beom Jang & Min-Soo Kwon

    2. Department of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, 14068, Hwaseong-Si, Gyeonggi-do, Republic of Korea

      Jong Wan Kim

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    1. Jong Wan Kim
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    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.

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    Correspondence to Min-Soo Kwon.

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    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).

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    Jong Wan Kim, Park, HS., You, MJ. 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

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