Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy

• Published in: Frontiers in immunology Vol. 12; p. 642420
• Main Authors: Agalave, Nilesh M, Mody, Prapti H, Szabo-Pardi, Thomas A, Jeong, Han S, Burton, Michael D
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 12.04.2021
• Subjects: astrocyte; Dorsal Root Ganglia; eIF4E; Immunology; microglia; mitochondrial respiration; T-cell; neuroimmune; eIF4E; T-cell; astrocyte; microglia; sex differences; Dorsal Root Ganglia; mitochondrial respiration
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.642420

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.