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.

尽管性别二态性越来越被认为是疼痛的一个重要因素，但女性特异性疼痛信号的研究还不够充分。在这里，我们报告了 IL-23 的给药在雌性而非雄性小鼠中产生机械性疼痛（机械性异常性疼痛），并且化疗引起的机械性疼痛在缺乏Il23或Il23r的雌性小鼠中选择性受损. IL-23 诱导的疼痛由雌激素促进，但被雄激素抑制，这表明性激素的参与。IL-23 需要 C 纤维伤害感受器和 TRPV1 来产生疼痛，但不直接激活伤害感受器神经元。值得注意的是，IL-23 需要从巨噬细胞释放 IL-17A 才能引起女性的机械性疼痛。低剂量 IL-17A 直接激活伤害感受器并仅在女性中诱发机械性疼痛。^{最后，TRPV1 +}伤害感受器中雌激素受体亚基 α (ERα) 的缺失消除了 IL-23 和 IL-17 诱导的女性疼痛。这些发现表明，IL-23/IL-17A/TRPV1 轴通过神经免疫相互作用调节女性特异性机械疼痛。我们的研究还揭示了免疫和神经元水平的性别二态性。