Expression of MHC II in DRG neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice

• Published in: PloS one 2024-02, Vol.19 (2), p.e0298396-e0298396
• Main Authors: Whitaker, Emily E, Mecum, Neal E, Cott, Riley C, Goode, Diana J
• Format: Article
• Language: English
• Subjects: Antimitotic agents; Antineoplastic agents; Biology and Life Sciences; Cancer; Care and treatment; Chemotherapy; Chills; Complications and side effects; Cytokines; Dorsal root ganglia; Gene expression; Genetic aspects; Health aspects; Major histocompatibility complex; Medicine and Health Sciences; Neurological research; Neurons; Paclitaxel; Polyneuropathies; Research and Analysis Methods; Social Sciences; T cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0298396

Chemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts cancer survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+ T cells are activated, and the extent cytokines released by CD4+ T cells target DRG neurons are unknown. Here, we are the first to detect major histocompatibility complex II (MHCII) protein in mouse DRG neurons and to find CD4+ T cells breaching the satellite glial cell barrier to be in close proximity to neurons, together suggesting CD4+ T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male and female mouse DRG but increased after PTX in small nociceptive neurons in only female DRG. Reducing one copy of MHCII in small nociceptive neurons decreased anti-inflammatory IL-10 and IL-4 producing CD4+ T cells in naïve male DRG and increased their hypersensitivity to cold. Administration of PTX to male and female mice that lacked one copy of MHCII in nociceptive neurons decreased anti-inflammatory CD4+ T cells in the DRG and increased the severity of PTX-induced cold hypersensitivity. Collectively, our results demonstrate expression of MHCII protein in mouse DRG neurons, which modulates cytokine producing CD4+ T cells in the DRG and attenuates cold hypersensitivity during homeostasis and after PTX treatment.