Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect that occurs in up to 63% of patients and has no known effective treatment. A majority of studies do not effectively assess sex differences in the onset and persistence of CIPN. Here we investigated the onset of CIPN, a point of therapeutic intervention where we may limit, or even prevent the development of CIPN. We hypothesized that cap-dependent translation mechanisms are important in early CIPN development and the bi-directional crosstalk between immune cells and nociceptors plays a complementary role to CIPN establishment and sex differences observed. In this study, we used wild type and eIF4E-mutant mice of both sexes to investigate the role of cap-dependent translation and the contribution of immune cells and nociceptors in the periphery and glia in the spinal cord during paclitaxel-induced peripheral neuropathy. We found that systemically administered paclitaxel induces pain-like behaviors in both sexes, increases helper T-lymphocytes, downregulates cytotoxic T-lymphocytes, and increases mitochondrial dysfunction in dorsal root ganglia neurons; all of which is eIF4E-dependent in both sexes. We identified a robust paclitaxel-induced, eIF4E-dependent increase in spinal astrocyte immunoreactivity in males, but not females. Taken together, our data reveals that cap-dependent translation may be a key pathway that presents relevant therapeutic targets during the early phase of CIPN. By targeting the eIF4E complex, we may reduce or reverse the negative effects associated with chemotherapeutic treatments.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and doselimiting complications in chemotherapy patients
Given that CIPN has an elusive etiology and the diverse array of cell types that could participate in CIPN development, we investigated whether there was a sexdependent role of eIF4E phosphorylation in dorsal root ganglion (DRG) sensory neuron metabolism, local immune cell populations, peripheral T-cell subpopulations, and spinal microglia and astrocytes
Compared to WT paclitaxel-treated mice, the eIF4ES209A paclitaxel-treated mice had significantly lower mechanical hypersensitivity (Figures 2B, D and Table 2) in both sexes. These findings indicate that eIF4E phosphorylation plays a protective role in the development of mechanical hypersensitivity after paclitaxel administration, but this protection is to a lesser extent in females
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and doselimiting complications in chemotherapy patients. There is limited data on sex differences in neuroimmune effects during CIPN Both clinical and preclinical investigations have reported conflicting observations ranging from marked sexual dimorphisms to no sex differences during CIPN (8–11). A more recent study showed that “primed” CD8+ T-cells, previously exposed to a chemotherapy agent, could prevent CIPN development when transferred to a new host (15). Based on these previous studies, we decided to assess the role of discrete T-cell subtypes: CD4+(Th1, Th2), T regulatory (Tregs), Effector (Teff), and activated cytotoxic T-lymphocytes (CD8+) in the draining lymph nodes of male and female mice after induction of CIPN
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