# Interleukin-6 as a keystone cytokine in experimental rat models of chemotherapy-induced peripheral neurotoxicity

## TL;DR

This study explores how the cytokine IL-6 contributes to nerve damage caused by chemotherapy in rats, suggesting it could be a key target for treatment.

## Contribution

The study identifies IL-6 as a central cytokine linking inflammation and chemotherapy-induced neurotoxicity in rat models.

## Key findings

- PTX-induced CIPN is associated with increased macrophage infiltration and distinct IL-6 expression patterns.
- OHP-induced CIPN shows elevated IL-6 and CCL2 expression in dorsal root ganglia.
- IL-6 and CXCL1 are suggested as critical inflammatory drivers in CIPN.

## Abstract

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one common side effect associated with antineoplastic agents. Despite its relevance, the underlying mechanisms remain poorly understood. In this study, we explored cytokines and macrophages that contribute to two chronic models of CIPN comparing paclitaxel (PTX)- and oxaliplatin (OHP)-induced CIPN in rats. To detect chemotherapy-induced sensory or neuronal abnormalities behavioral tests, pathological and morphometric analysis were used. To investigate systemic inflammation, a panel including IL-6, IL-1β, IL-2, IL-10, GRO/KC(CXCL1), TNFα, IFNγ were tested in serum. Besides, we analyzed dorsal root ganglia (DRG), caudal nerves and spinal cord mRNA expression of a panel of pro-inflammatory markers IL-6, CCL2 and NLRP3, as well as caudal macrophage infiltration. We evidenced a remarkable difference in caudal macrophage infiltration in PTX- vs. OHP-treated rats, which was associated with serum CXCL1 and to a different IL-6 expression pattern in serum, DRG, spinal cord and caudal nerve. Moreover, CCL2, NLRP3 upregulation was also increased in the caudal nerves in PTX-treated animals. On the contrary, OHP induced IL-6 and CCL2 expression in DRG. Since our results suggest that CXCL1 or IL-6 could be considered as critical lynchpins between inflammation pain and CIPN, targeting early inflammatory events could be a promising therapeutic approach.

The online version contains supplementary material available at 10.1038/s41598-025-34830-6.