Time Course of Peripheral and Central Immune System Alterations in Paclitaxel-Treated Mice: Possible Involvement of Dysf
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XPERIMENTAL ARTICLES
Time Course of Peripheral and Central Immune System Alterations in Paclitaxel-Treated Mice: Possible Involvement of Dysfunctional Microglia Jong Wan Kima, b, 1, Hyun-Sun Parka, 1, Min-Jung Youa, Bohyun Yanga, Kyu Beom Janga, and Min-Soo Kwona, 2 a
Department of Pharmacology, School of Medicine, CHA University, CHA BIO COMPLEX, 335 Pangyo, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488 Republic of Korea bDepartment of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong-Si, Gyeonggi-do 14068 Republic of Korea Received July 30, 2019; revised October 14, 2019; accepted December 19, 2019
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. Keywords: microglia, paclitaxel, pain, lipofuscin DOI: 10.1134/S1819712420020063
INTRODUCTION Although chronic pain is a major factor in deteriorating quality of life, currently available therapies are limited to nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids [1]. Chronic pain can be caused into various types such as spinal cord injury, peripheral nerve damage, cancer pain, and neuropathic pain and they have each pathophysiology or share common pathophysiology [2]. Generally, chronic pain fail to relieve acute pain caused by acute inflammation, lead to persistent inflammation, eventually causes central sensitization in the central nervous system. This is a major difference from acute pain. In this regard, it has been reported that neuroin1 These authors contributed equally to the manuscript. 2 Corresponding author; addre
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