Role of Toll-like receptor 4 signaling in mast cell-mediated migraine pain pathway
Role of Toll-like receptor 4 signaling in mast cell-mediated migraine pain pathway
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DOI：
10.1177/1744806919867842
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发表时间：
2019-08-01
期刊：
影响因子：
3.3
通讯作者：
Yaksh, Tony L.
中科院分区：
文献类型：
--
作者：
Ramachandran, Roshni;Wang, Zhenping;Yaksh, Tony L.
脑膜肥大细胞脱颗粒导致三叉神经血管传入处理的敏化被认为是偏头痛通路的机制之一。最近的研究表明 Toll 样受体 4 (TLR4) 可能参与中枢敏化的信号传导状态。使用由化合物 48/80（2 mg/kg，腹膜内）肥大细胞脱粒产生的厌恶光小鼠模型（用作偏头痛患者畏光的替代标记），我们检查了 TLR4 在偏头痛样行为和神经元激活中的作用。使用两室明/暗盒，我们发现在雄性和雌性 C57Bl/6 小鼠中施用化合物 48/80 会产生持续长达 2 小时的光厌恶，并且用舒马普坦（1 mg/kg，腹腔注射）预处理可靠地防止了这种效应。 TLR4 的基因缺失和用 TAK-242（3 mg/kg，腹膜内注射）的药理学阻断可逆转化合物 48/80 对雄性而非雌性的光厌恶作用。通过评估突变小鼠的下游信号通路，我们发现 TLR4 介导的光厌恶依赖于骨髓分化初级反应基因 88，而不是包含 Toll-interleukin-1 受体结构域的接头诱导的干扰素-β 信号传导。在单独的组中，在化合物48/80后10分钟处死的雄性小鼠显示野生型尾核中诱发的p-细胞外信号调节激酶(+)神经元的发生率显着增加，但Tlr4(-/-)小鼠或用舒马曲坦预处理的小鼠则没有。因此，这项研究为 TLR4 信号通过 MyD88 参与启动和维持小鼠偏头痛样行为和尾核神经元激活提供了第一个证据。
Degranulation of meningeal mast cells leading to the sensitization of trigeminal vascular afferent processing is believed to be one of the mechanisms underlying the migraine pain pathway. Recent work suggests that Toll-like receptor 4 (TLR4) may be involved in signaling states of central sensitization. Using a murine model of light aversion produced by compound 48/80 (2 mg/kg, intraperitoneal) mast cell degranulation, employed as a surrogate marker for photophobia observed in migraineurs, we examined the role of TLR4 in migraine-like behavior and neuronal activation. Using a two-chambered light/dark box, we found that compound 48/80 administration in male and female C57Bl/6 mice produced light aversion lasting up to 2 h, and that pre-treatment with sumatriptan (1 mg/kg, i.p.) reliably prevented this effect. Genetic deletion and pharmacological blockade of TLR4 with TAK-242 (3 mg/kg, i.p.) reversed the light aversive effects of compound 48/80 in males but not in females. Assessing the downstream signaling pathway in mutant mice, we found that the TLR4-mediated, light aversion was dependent upon myeloid differentiation primary response gene 88 but not Toll-interleukin-1 receptor domain-containing adapter-inducing interferon-beta signaling. In separate groups, male mice sacrificed at 10 min following compound 48/80 revealed a significant increase in the incidence of evoked p-extracellular signal-regulated kinases (+) neurons in the nucleus caudalis of wild type but not Tlr4(-/-) mice or in mice pre-treated with sumatriptan. This study thus provides the first evidence for involvement of TLR4 signaling through MyD88 in initiating and maintaining migraine-like behavior and nucleus caudalis neuronal activation in the mouse.