Sexual dimorphism of neuroimmune interactions in temporomandibular joint disorders pain: contribution of a newly identified female-specific pain signaling axis IL23/IL17A/TRPV1

摘要 颞下颌关节紊乱病(TMJD)是最常见的慢性口面部疼痛形式。TMJD影响 大约有1000万美国人，女性的患病率是男性的3倍。此外， 临床研究表明，女性TMJD患者比男性患者表现出更大的疼痛。不幸的是，很精确 对TMJD疼痛的性别二型性的机制理解在很大程度上仍不清楚，阻碍了 试图开发女性选择的疼痛疗法，并改善女性患者的疼痛管理。我们 新近发现IL23/IL17A/TRPV1信号轴通过 神经免疫相互作用，特别是在雌性幼稚小鼠和有神经损伤的雌性小鼠中。在 免疫细胞水平，白介素23(IL23)刺激女性释放白介素17A(IL17A)，但不 男性，巨噬细胞。释放的IL17A仅在雌性小鼠中通过激活TRPV1-1引起机械性疼痛 表达背根神经节(DRG)感觉神经元。这些发现是向前迈出的关键一步 理解疼痛中的性别差异。我们母公司R01的总体目标是评估 三叉神经节感觉神经元中的TRPV1和TRPA1参与了TMJD痛。在这激动人心的 行政补充，我们将确定这种女性特有的疼痛信号IL23/IL17A/TRPV1 巨噬细胞-感觉神经元的串扰导致了TMJD疼痛的性别二型性，这是 由三叉神经感觉系统介导，有其独特的病因。我们相信这项提议将 极大地补充了我们的母机R01的目标。更重要的是，成功解决建议的 研究将极大地增强我们对为什么女性患TMJD疼痛和 经历比男性更严重的TMJD疼痛，从而推动我们对合理目标的新的追求 女性TMJD疼痛的预防和治疗。

Abstract Temporomandibular joint disorders (TMJD) are the most common form of chronic orofacial pain. TMJD affects approximately 10 million Americans and is up to 3 times more prevalent in women than in men. Moreover, clinical studies demonstrated that female TMJD patients exhibit greater pain than males. Unfortunately, precise mechanistic understanding of sexual dimorphism of TMJD pain remains largely unknown, hindering the attempts to develop female-selective pain therapies and improve pain management for female patients. We recently discovered that IL23/IL17A/TRPV1 signaling axis regulates somatosensory mechanical pain via neuro-immune interactions specifically in female naïve mice and in female mice with nerve injuries. At the immune cell level, interleukin 23 (IL23) stimulates the release of interleukin 17A (IL17A) from female, but not male, macrophages. Released IL17A evokes mechanical pain only in female mice via activation of TRPV1- expressing dorsal root ganglion (DRG) sensory neurons. These findings constitute a critical step forward in understanding of sex differences in pain. The overall goal of our parent R01 is to assess the extent to which TRPV1 and TRPA1 in trigeminal ganglion (TG) sensory neurons contribute to TMJD pain. In this exciting Administrative Supplement, we will determine whether this female-specific pain signaling IL23/IL17A/TRPV1 involving macrophage-sensory neuron crosstalk contributes to the sexual dimorphism of TMJD pain, which is mediated by trigeminal sensory system and has its own distinct etiologies. We believe this proposal will significantly complement our goal of the parent R01. More importantly, successfully addressing the proposed studies will greatly enhance our understanding why women are at a greater risk for developing TMJD pain and experience more severe TMJD pain than men, thereby advancing our quest for rationally-targeted new preventions and treatments for TMJD pain in women.