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.
Xin Luo  1 ,  Ouyang Chen  2 ,  Zilong Wang  3 ,  Sangsu Bang  3 ,  Jasmine Ji  3 ,  Sang Hoon Lee  4 ,  Yul Huh  2 ,  Kenta Furutani  3 ,  Qianru He  3 ,  Xueshu Tao  3 ,  Mei-Chuan Ko  5 ,  Andrey Bortsov  3 ,  Christopher R Donnelly  3 ,  Yong Chen  6 ,  Andrea Nackley  7 ,  Temugin Berta  4 ,  Ru-Rong Ji  8
Affiliations
  • 1. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address: [email protected].
  • 2. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
  • 3. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
  • 4. Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 5. Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • 6. Department of Neurology, Duke University Medical Center, Durham, NC, USA.
  • 7. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
  • 8. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC, USA. Electronic address: [email protected].
PMID: 34473953 DOI: 10.1016/j.neuron.2021.06.015
Abstract

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.
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