Department of Neurology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
Headache. 2023 Sep;63(8):1045-1060. doi: 10.1111/head.14599. Epub 2023 Aug 4.
To investigate the effect of the aryl hydrocarbon receptor (AHR)/regulatory T cell (Treg)/T-helper 17 (Th17) cell pathway on the pathogenesis of migraine.
Migraine is a disabling neurovascular disease that imposes an enormous burden on both individuals and society. The pathophysiological mechanisms of migraine remain controversial. Recent studies have suggested that immune dysfunction may be involved in the pathogenesis of migraine. The AHR, a receptor expressed on most immune cells, has been implicated in the occurrence of many autoimmune diseases; however, whether it is involved in the pathogenesis of migraine is unclear.
A chronic migraine rat model was established through repeated intraperitoneal injection of nitroglycerin (NTG). The mechanical and thermal pain thresholds were assessed using von Frey filaments and radiant heat. Next, the protein expression levels of AHR in the trigeminal nucleus caudalis (TNC) region of chronic migraine (CM)-like rats were quantified and the changes in Treg/Th17-related transcription factors and inflammatory factors in the TNC were explored. To determine the role of AHR in CM, we examined the effects of the AHR agonist 2-(1'-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and AHR antagonist CH-223191 on pain behavior, c-Fos, calcitonin gene-related peptide (CGRP), AHR, and Treg/Th17-related factor expression in CM-like rats.
Repeated administration of NTG significantly enhanced nociceptive hypersensitivity and increased expression of c-Fos and CGRP in rats, while AHR was significantly decreased in the TNC. In addition, the expression of the transcription factor forkhead box protein P3 and the signal transducer and activator of transcription 5 decreased significantly. In contrast, the expression of the transcription factor retinoic acid receptor-related orphan receptor γ t and signal transducer and activator of transcription 3 were significantly increased. Moreover, the mRNA level of transforming growth factor beta-1 was decreased, while that of interleukin (IL)-10 and IL-22 was increased in the TNC. The AHR agonist ITE alleviated migraine-like pain behaviors in rats, activated the AHR signaling pathway, and improved the imbalance of Treg/Th17-related transcription factors and inflammatory factors. Conversely, the AHR antagonist CH-223191 did not alleviate migraine-like pain behaviors in rats; and even exacerbated them.
The AHR participates in the development of CM by regulating Treg/Th17-related homeostasis. Therefore, treatments targeting the AHR/Treg/Th17 signaling pathway could be new effective interventions for CM treatment.
探讨芳香烃受体（AHR）/调节性 T 细胞（Treg）/辅助性 T 细胞 17（Th17）通路在偏头痛发病机制中的作用。
偏头痛是一种使人丧失能力的血管性疾病，给个人和社会带来了巨大的负担。偏头痛的病理生理机制仍存在争议。最近的研究表明，免疫功能障碍可能与偏头痛的发病机制有关。AHR 是一种在大多数免疫细胞上表达的受体，它与许多自身免疫性疾病的发生有关；然而，它是否参与偏头痛的发病机制尚不清楚。
通过反复腹腔注射硝化甘油（NTG）建立慢性偏头痛大鼠模型。使用 von Frey 纤维和辐射热评估机械和热痛阈值。接下来，定量分析慢性偏头痛（CM）样大鼠三叉神经尾核（TNC）区 AHR 的蛋白表达水平，并探讨 TNC 中 Treg/Th17 相关转录因子和炎症因子的变化。为了确定 AHR 在 CM 中的作用，我们研究了 AHR 激动剂 2-（1'-吲哚-3'-羰基）-噻唑-4-羧酸甲酯（ITE）和 AHR 拮抗剂 CH-223191 对 CM 样大鼠疼痛行为、c-Fos、降钙素基因相关肽（CGRP）、AHR 和 Treg/Th17 相关因子表达的影响。
NTG 的重复给药显著增强了大鼠的痛觉过敏，增加了大鼠的 c-Fos 和 CGRP 的表达，而 TNC 中的 AHR 明显减少。此外，叉头框蛋白 P3 和信号转导和转录激活因子 5 的转录因子表达显著降低。相反，维甲酸受体相关孤儿受体 γ t 和信号转导和转录激活因子 3 的转录因子表达显著增加。此外，TNC 中转化生长因子-β 1 的 mRNA 水平降低，白细胞介素（IL）-10 和 IL-22 的水平升高。AHR 激动剂 ITE 减轻了大鼠偏头痛样疼痛行为，激活了 AHR 信号通路，并改善了 Treg/Th17 相关转录因子和炎症因子的失衡。相反，AHR 拮抗剂 CH-223191 并没有减轻大鼠偏头痛样疼痛行为，甚至加重了它们。
AHR 通过调节 Treg/Th17 相关内稳态参与 CM 的发展。因此，针对 AHR/Treg/Th17 信号通路的治疗可能是偏头痛治疗的新有效干预措施。
