Meningeal Nociceptor-Immune Signaling in Migraine

偏头痛是一种多因素的疾病，其特征是反复发作的严重头痛， 全球残疾的原因。虽然偏头痛没有明确的病理生理学起源，但一个主要的理论表明， 硬脑膜的无菌神经源性炎症是驱动持续性脑膜炎的机制 伤害性感受，导致发作时头痛。然而，神经源性的血管成分 由激活的伤害感受器的外周末端释放的神经肽介导的炎症-增加 血管渗透性和血管舒张-现在被认为是既不必要，也不充分的偏头痛 头痛的成因这就提出了一个问题，脑膜神经源性炎症是否与 偏头痛，如果是这样的话，其他神经驱动的炎症过程是否也起作用。越来越多 的证据也指出了神经源性炎症中的免疫成分，例如伤害感受器的激活， 促进免疫细胞募集并调节其功能反应。伤害感受器的激活， 然而，也可以抑制炎性免疫应答。这个合作项目将联合收割机结合我们的 脑膜伤害感受和偏头痛（Levy）以及伤害感受器之间的功能相互作用方面的专业知识 和免疫细胞（Chiu），以探讨偏头痛的非血管炎症机制，涉及双向 脑膜伤害感受器和脑膜免疫之间的通信，驱动偏头痛。我们 提出新的强大的方法组合，包括光遗传学，活体双光子显微镜，流动 流式细胞术、多重细胞因子阵列和疼痛行为分析来研究脑膜神经免疫 在模拟偏头痛发作（急性刺激）和严重发作（长期刺激）的条件下的相互作用 刺激）。我们将首先描述脑膜免疫反应和相关的偏头痛样疼痛行为 其在Nav1.8谱系脑膜伤害感受器的选择性光遗传学激活后发展（Aim 1）。然后， 基于初步的数据，我们将确定脑膜中性粒细胞和T细胞在 调节这些与偏头痛相关的疼痛行为（目标2）。总的来说，这些实验可以提供一个 更好地理解神经源性炎症在偏头痛病理生理学中的作用， 作为未来探索脑膜神经免疫机制的实验基础 串扰和进一步测试特定的免疫细胞和相关的促炎介质作为潜在的 治疗偏头痛的目标。

Migraine is a multifactorial disorder characterized by recurrent attacks of severe headache and is one of the top causes of global disability. Although migraine has no clear pathophysiological origin, a major theory implicates sterile neurogenic inflammation of the cranial dural meninges as the mechanism that drives persistent meningeal nociception, resulting in the headache during an attack. However, the vascular components of neurogenic inflammation mediated by neuropeptides released from peripheral terminals of activated nociceptors - increased vascular permeability and vasodilation - are now considered neither necessary nor sufficient for migraine headache genesis. This raises the question of whether meningeal neurogenic inflammation is relevant to migraine pain, and if so, could other neurogenically-driven inflammatory processes play a role. A growing body of evidence also points to an immune component in neurogenic inflammation, such that activation of nociceptors promotes immune cell recruitment and regulates their functional responses. Activation of nociceptors, nevertheless, can also suppress inflammatory immune responses. This collaborative project will combine our expertise in meningeal nociception and migraine pain (Levy) and functional interactions between nociceptors and immune cells (Chiu) to explore a non-vascular inflammatory mechanism of migraine involving bidirectional communication between meningeal nociceptors and meningeal immunity that drives migraine headache. We propose novel combinations of powerful methods, including optogenetics, intravital 2-photon microscopy, flow cytometry, multiplex cytokine arrays, and analysis of pain behaviors to study meningeal neuroimmune interactions under conditions that mimic migraine attack onset (acute stimulation) and a severe attack (prolonged stimulation). We will first characterize the meningeal immune response and related migraine-like pain behaviors that develop following selective optogenetic activation of Nav1.8-lineage meningeal nociceptors (Aim 1). Then, based on preliminary data, we will determine the relative contribution of meningeal neutrophils and T cells in mediating these migraine-related pain behaviors (Aim 2). Collectively, these experiments could provide a dramatically better understanding of the role of neurogenic inflammation in migraine pathophysiology and serve as an experimental foundation for future explorations of mechanistic insights into meningeal neuroimmune crosstalk and further testing of specific immune cells and related proinflammatory mediators as potential therapeutic targets for migraine pain.