Goode, D. J. | bioRxiv Science

bioRxiv2023

Novel expression of major histocompatibility complex II in dorsal root ganglion neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice

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 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 found novel expression of functional major histocompatibility complex II (MHCII) protein in DRG neurons, and CD4+ T cells in close proximity to DRG neurons, together suggesting CD4+ T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male mouse DRG regardless of PTX, while MHCII is induced in small nociceptive neurons in female DRG after PTX. Accordingly, reducing MHCII in small nociceptive neurons increased hypersensitivity to cold only in naive male mice, but increased severity of PTX-induced cold hypersensitivity in both sexes. Collectively, our results demonstrate expression of MHCII on DRG neurons and a functional role during homeostasis and inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/535136v3_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@46400dorg.highwire.dtl.DTLVardef@17335eorg.highwire.dtl.DTLVardef@12d8e87org.highwire.dtl.DTLVardef@1e8562f_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with Biorender.com SummaryNovel expression of functional MHCII protein was detected on the surface of DRG neurons, suggesting a potential mechanism for CD4+ T cell activation and targeted cytokine release. Reducing MHCII from a subpopulation of neurons known to contribute to CIPN increased the severity of PTX-induced cold hypersensitivity in female and male mice.

immunology↗

bioRxiv2022

Ovariectomy increases paclitaxel-induced mechanical hypersensitivity and reduces anti-inflammatory CD4+ T cells in the dorsal root ganglion of female mice

Chemotherapy is often dose limiting due to the emergence of a debilitating neuropathy. IL-10 and IL-4 are protective against peripheral neuropathy, yet the cell source is unknown. Using flow cytometry, we found that naive females had a greater frequency of anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG) than males. In response to paclitaxel, females had reduced hypersensitivity and a greater frequency of anti-inflammatory CD4+ T cells (FoxP3, IL-10, IL-4) in the DRG than ovariectomized and male mice. These findings support a model in which estrogen promotes antiinflammatory CD4+ T cells in female DRG to suppress peripheral neuropathy. HighlightsO_LICD4+ T cells are present in the dorsal root ganglion of naive and paclitaxel-treated male and female mice. C_LIO_LINaive female mice have a higher frequency of CD4+ T cells in the dorsal root ganglion compared to ovariectomized female and male mice. C_LIO_LIPaclitaxel induces more severe mechanical hypersensitivity in ovariectomized female and male mice compared to estrogen-competent female mice. C_LIO_LIPaclitaxel increases pro- and anti-inflammatory CD4+ T cells in the dorsal root ganglion of both male and female mice, but the increase in anti-inflammatory T cells is more robust in female mice. C_LIO_LIOvariectomy reduces cytokine-producing CD4+ T cells in the dorsal root ganglion and prevents the PTX-induced increase in cytokine-producing CD4+ T cells in the dorsal root ganglion. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/476262v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@235050org.highwire.dtl.DTLVardef@6decadorg.highwire.dtl.DTLVardef@cd7b1borg.highwire.dtl.DTLVardef@4d5b43_HPS_FORMAT_FIGEXP M_FIG Image created with Biorender.com C_FIG

immunology↗