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.