Ovariectomy Reduces Anti-inflammatory CD4+ T Cells in the Dorsal Root Ganglion of NaïVe and Paclitaxel-treated Female Mice

Abstract

Chemotherapeutic agents are often a life-saving cancer treatment, but the development of chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity. The prevalence of CIPN is greater than 68%, with post-menopausal women and patients taking anti-estrogens and aromatase inhibitors having increased risk. T cell deficient male and female mice have prolonged paclitaxel (PTX)-induced mechanical hypersensitivity. Sex-specific hormones can alter the T cell response contributing to differential susceptibilities to disease. As a result of estrogen, females have more CD4+ T cells in blood and tissues, but it is unknown if this is true in the DRG. To have a better understanding of the role of CD4+ T cells in mouse DRG, we characterized pro- and anti-inflammatory CD4+ T cells in naive and PTX-treated male, female, and ovariectomized (OVX) mice. We used multi-color flow cytometry to determine pro- and anti-inflammatory CD4+ T cell subsets in the DRG of naive and PTX-treated male, female, and OVX mice. Findings show that CD4+ T cells are present in the DRG of naive and PTX-treated male and female mice. Female mice had a greater frequency of CD4+ T cells in the DRG than OVX and male mice. Although the frequencies of cytokine-producing CD4+ T cells in the DRG differ between male and female, the majority of CD4+ T cells were anti-inflammatory cells that increased after PTX administration. PTX induced a robust increase in FoxP3, IL-10, and IL-4 producing CD4+ T cells in the DRG of female mice, but not in OVX or male mice. Our data demonstrate that CD4+ T cells in the DRG of estrogen-competent female mice secrete anti-inflammatory cytokines (IL-10 and IL-4), which are known to reduce CIPN. These findings support a model in which estrogen promotes anti-inflammatory CD4+ T cells in female DRG to suppress peripheral neuropathy. Grant support from National Institutes of Health NIGMS P20GM103643.