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

颞下颌关节疾病疼痛中神经免疫相互作用的性别二态性：新发现的女性特异性疼痛信号轴 IL23/IL17A/TRPV1 的贡献

• 批准号: 10596384
• 负责人: Yong Chen
• 金额: $ 12.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596384
• 关键词: Address; Administrative Supplement; Affect; Afferent Neurons; American; Attenuated; Blood; Brain-Derived Neurotrophic Factor; Cells; Characteristics; Chronic; Clinical Research; Complement; Data; Development; Etiology; Exhibits; Female; Goals; Immune; Immune Targeting; Immune signaling; Inflammatory; Injections; Injury; Interleukin-17; Interleukins; Intramuscular; Knock-out; Knowledge; Libido; MAP Kinase Gene; Masseter Muscle; Masticatory muscles; Mechanics; Mediating; Methods; Microglia; Migraine; Mus; Neuraxis; Neuroimmune; Neurons; Nociception; Orofacial Pain; Pain; Pain management; Parents; Patients; Performance; Play; Predisposition; Prevention; Progress Reports; Purinoceptor; Quality of life; Research; Risk; Role; Sex Differences; Signal Transduction; Spinal; Spinal Cord; Spinal Ganglia; Structure of trigeminal ganglion; TLR4 gene; TRPV1 gene; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Time; Tissues; Toothache; Trigeminal System; Woman; chemotherapy; chronic painful condition; comorbidity; cytokine; disorder prevention; experience; improved; inflammatory pain; interleukin-23; joint inflammation; macrophage; male; men; mouse model; nerve injury; novel; p38 Mitogen Activated Protein Kinase; pain sensitivity; pain signal; painful neuropathy; prevent; psychosocial; receptor; sensory system; sex; sexual dimorphism; somatosensory; success

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.

抽象的 颞下颌关节紊乱病 (TMJD) 是慢性口面部疼痛的最常见形式。 大约有 1000 万美国人，女性患病率是男性的 3 倍。 不幸的是，临床研究表明，女性 TMJD 患者比男性患者表现出更大的疼痛。 对 TMJD 疼痛性别二态性的机制理解仍然很大程度上未知，这阻碍了 我们尝试开发女性选择性疼痛疗法并改善女性患者的疼痛管理。 最近发现IL23/IL17A/TRPV1信号轴通过调节体感机械疼痛 神经免疫相互作用，特别是在雌性幼鼠和神经损伤的雌性小鼠中。 免疫细胞水平，白细胞介素23（IL23）刺激女性释放白细胞介素17A（IL17A），但不 雄性巨噬细胞释放的 IL17A 仅通过激活 TRPV1- 在雌性小鼠中引起机械性疼痛。 表达背根神经节（DRG）感觉神经元，这些发现构成了关键的一步。 了解疼痛的性别差异 我们家长 R01 的总体目标是评估疼痛的程度。 三叉神经节 (TG) 感觉神经元中的 TRPV1 和 TRPA1 会导致 TMJD 疼痛。 行政补充，我们将确定这种女性特有的疼痛信号IL23/IL17A/TRPV1是否 涉及巨噬细胞-感觉神经元的串扰导致了 TMJD 疼痛的性别二态性，即 由三叉神经感觉系统介导，并有其独特的病因，我们相信该提议将。 显着补充我们母版 R01 的目标，更重要的是，成功解决了拟议的问题。 研究将极大地加深我们对为什么女性患颞下颌关节病的风险更大的理解 经历比男性更严重的颞下颌关节紊乱病疼痛，从而推进我们对合理目标新疗法的探索 女性颞下颌关节病疼痛的预防和治疗。

项目成果

Sensory Neuron-TRPV4 Modulates Temporomandibular Disorder Pain Via CGRP in Mice.

• DOI: 10.1016/j.jpain.2022.12.001
• 发表时间: 2022-12
• 期刊: The journal of pain
• 作者: A. Suttle;Peng Wang;Fabiana C. Dias;Qiaojuan Zhang;Yuhui Luo;Lauren Simmons;A. Bortsov;I. Tchivileva;A. Nackley;Yong Chen

Silencing of TRPV4-expressing sensory neurons attenuates temporomandibular disorders pain.

• DOI: 10.1177/17448069231185696
• 发表时间: 2023-01
• 期刊: Molecular pain
• 影响因子: 3.3

Transient Receptor Potential (TRP) Ion Channels in Orofacial Pain.

• DOI: 10.1007/s12035-021-02284-2
• 发表时间: 2021-06
• 期刊: Molecular neurobiology
• 影响因子: 5.1
• 作者: Luo Y;Suttle A;Zhang Q;Wang P;Chen Y
• 通讯作者: Chen Y

Involvement of Sensory Neurone-TRPV4 in Acute and Chronic Itch Behaviours.

• DOI: 10.2340/actadv.v102.1621
• 发表时间: 2022-02-22
• 期刊: Acta dermato-venereologica
• 影响因子: 3.6

TMEM100, a regulator of TRPV1-TRPA1 interaction, contributes to temporomandibular disorder pain.

• DOI: 10.3389/fnmol.2023.1160206
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Wang, Peng;Zhang, Qiaojuan;Dias, Fabiana C.;Suttle, Abbie;Dong, Xinzhong;Chen, Yong
• 通讯作者: Chen, Yong