Zhang Jintao, Czerpaniak Katherine, Huang Liang, Liu Xuemei, Cloud Megan E, Unsinger Jacqueline, Hotchkiss Richard S, Li Daizong, Cao Yu-Qing
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States.
Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States. Dr. Huang is now with the Department of Anesthesiology, New York University Langone Health, New York University Grossman School of Medicine, New York, NY, United States.
Pain. 2020 Jun;161(6):1381-1398. doi: 10.1097/j.pain.0000000000001818.
Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many proinflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders. In a mouse model of chronic migraine, we observed that repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration doubled the number of CD3 T cells in the trigeminal ganglia without altering the number of Treg cells, suggesting a deficiency in Treg-mediated immune homeostasis. We treated mice with low-dose interleukin-2 (ld-IL2) to preferentially expand and activate endogenous Treg cells. This not only prevented the development of NTG-induced persistent sensitization but also completely reversed the established facial skin hypersensitivity resulting from repeated NTG administration. The effect of ld-IL2 was independent of mouse sex and/or strain. Importantly, ld-IL2 treatment did not alter basal nociceptive responses, and repeated usage did not induce tolerance. The therapeutic effect of ld-IL2 was abolished by Treg depletion and was recapitulated by Treg adoptive transfer. Furthermore, treating mice with ld-IL2 1 to 7 days after mild traumatic brain injury effectively prevented as well as reversed the development of behaviors related to acute and chronic post-traumatic headache. In a model of medication overuse headache, Ld-IL2 completely reversed the cutaneous hypersensitivity induced by repeated administration of sumatriptan. Collectively, this study identifies ld-IL2 as a promising prophylactic for multiple headache disorders with a mechanism distinct from the existing treatment options.
头痛疾病非常普遍且使人衰弱，治疗选择有限。先前的研究表明，许多促炎免疫细胞参与头痛的病理生理过程。鉴于调节性T（Treg）细胞在维持免疫稳态中公认的作用，我们推测增强Treg功能可能有效治疗多种头痛疾病。在慢性偏头痛小鼠模型中，我们观察到反复给予硝酸甘油（NTG，患者偏头痛的可靠诱因）使三叉神经节中CD3 T细胞数量增加一倍，而Treg细胞数量未改变，提示Treg介导的免疫稳态存在缺陷。我们用低剂量白细胞介素-2（ld-IL2）治疗小鼠，以优先扩增和激活内源性Treg细胞。这不仅预防了NTG诱导的持续性致敏的发展，还完全逆转了因反复给予NTG而导致的已确立的面部皮肤超敏反应。ld-IL2的作用与小鼠性别和/或品系无关。重要的是，ld-IL2治疗未改变基础伤害性反应，反复使用也未诱导耐受性。Treg细胞耗竭消除了ld-IL2的治疗效果，而Treg细胞过继转移则重现了该效果。此外，在轻度创伤性脑损伤后1至7天用ld-IL2治疗小鼠可有效预防并逆转与急性和慢性创伤后头痛相关行为的发展。在药物过度使用性头痛模型中，ld-IL2完全逆转了反复给予舒马曲坦所诱导的皮肤超敏反应。总体而言，本研究确定ld-IL2是一种有前景的预防多种头痛疾病的药物，其作用机制与现有治疗选择不同。
