Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy

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.

Toxicity in Peripheral Nerves: An Overview

“…Conventionally it is considered as a permanent and irreversible toxic effect. In CIPN, ongoing late immune mechanisms are discussed, which can kindle the persistence or even worsening of the neuropathy [ 26 , 27 ].…”

Inducible co-stimulatory molecule (ICOS) alleviates paclitaxel-induced neuropathic pain via an IL-10-mediated mechanism in female mice

“…Since we observed a resolution of mechanical allodynia in the ICOS-treated animals, we next examined glial cell changes in the DRG and the spinal cord [ 12 , 43 , 47 , 48 ]. Gliosis is a sign of injury or stress to the tissue, where the cells become hyperactive and change morphology [ 49 ].…”

Inducible co-stimulatory molecule (ICOS) alleviates Paclitaxel induced peripheral neuropathy via an IL-10-mediated mechanism in female mice

“…Since we observed a resolution of mechanical allodynia in the ICOS-treated animals, we next examined glial cell changes in the DRG and the spinal cord [1; 29; 35; 46].…”

“…Paclitaxel causes neurotoxicity by accumulating in the dorsal root ganglia (DRG) and in the peripheral nerves impairing axonal transport and causing mitochondrial dysfunction that is linked to the neuropathy [1; 12; 13; 15; 38; 39; 42; 47]. It is now well-accepted that the immune system can play an active role in modulating chronic pain progression and resolution [24; 55].…”

“…It is now well-accepted that the immune system can play an active role in modulating chronic pain progression and resolution [24; 55]. Neuro-immune interactions occur in CIPN, and both the adaptive and innate immune systems play an essential role in the progression and resolution of neuropathic pain [1; 19; 24]. For instance, immune cells have been shown to secrete both pro- and anti-inflammatory cytokines such as IL-6, IL-5, IL-4, IL-10, IFN γ and TNFα that can interact with neurons and regulate chronic pain [7; 30; 44; 63].…”