IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice

Neuron. 2021 Sep 1;109(17):2691-2706.e5. doi: 10.1016/j.neuron.2021.06.015. Epub 2021 Jul 19.


Although sex dimorphism is increasingly recognized as an important factor in pain, female-specific pain signaling is not well studied. Here we report that administration of IL-23 produces mechanical pain (mechanical allodynia) in female but not male mice, and chemotherapy-induced mechanical pain is selectively impaired in female mice lacking Il23 or Il23r. IL-23-induced pain is promoted by estrogen but suppressed by androgen, suggesting an involvement of sex hormones. IL-23 requires C-fiber nociceptors and TRPV1 to produce pain but does not directly activate nociceptor neurons. Notably, IL-23 requires IL-17A release from macrophages to evoke mechanical pain in females. Low-dose IL-17A directly activates nociceptors and induces mechanical pain only in females. Finally, deletion of estrogen receptor subunit α (ERα) in TRPV1+ nociceptors abolishes IL-23- and IL-17-induced pain in females. These findings demonstrate that the IL-23/IL-17A/TRPV1 axis regulates female-specific mechanical pain via neuro-immune interactions. Our study also reveals sex dimorphism at both immune and neuronal levels.

Keywords: IL-17; IL-23; dorsal root ganglion; estrogen receptor α; human; macrophage; mechanical allodynia; nociceptor; nonhuman primate; sex dimorphism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Humans
  • Interleukin-17 / metabolism*
  • Interleukin-17 / pharmacology
  • Interleukin-23 / metabolism*
  • Interleukin-23 / pharmacology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Fibers, Unmyelinated / metabolism
  • Nerve Fibers, Unmyelinated / physiology
  • Nociceptive Pain / metabolism*
  • Nociceptive Pain / physiopathology
  • Nociceptors / drug effects
  • Nociceptors / metabolism*
  • Nociceptors / physiology
  • Sex Factors
  • Signal Transduction
  • TRPV Cation Channels / metabolism*


  • Estrogen Receptor alpha
  • Interleukin-17
  • Interleukin-23
  • TRPV Cation Channels
  • TRPV1 protein, mouse