Meningeal Nociceptor-Immune Signaling in Migraine

点击翻译按钮获取中文摘要

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.