2. Academic Validation
  3. IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice

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

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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