[Advances in innate immune-mediated neuroinflammatory mechanisms of migraine]

Migraine is a highly disabling neurological disorder in which activation of the trigeminovascular system and the ensuing peripheral and central sensitization are major pathological foundations for pain initiation, recurrent attacks, and disease chronification. In recent years, innate immune-mediated sterile neuroinflammation has emerged as a key mechanism linking trigeminal neurovascular system activation to maladaptive remodeling of nociceptive pathways. During the early phase of a migraine attack, trigeminal nerve endings release calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide, and substance P, thereby inducing meningeal vasodilation, plasma protein extravasation, mast cell degranulation, and immune-cell recruitment, which collectively enhance the excitability of peripheral nociceptors. These peripheral inflammatory signals are subsequently transmitted to the spinal trigeminal nucleus caudalis and higher-order central nervous system regions, where they drive sustained activation of microglia and astrocytes, disruption of neurotransmitter homeostasis, and remodeling of neuronal excitability, ultimately maintaining central sensitization. Repeated stimulation may convert a transient neuroimmune response into persistent low-grade activation. Concerted glial activation, blood-brain barrier dysfunction, and positive-feedback interactions between neuropeptides and inflammatory mediators are thought to drive migraine chronification. At the molecular level, endogenous danger-associated molecular patterns, including extracellular adenosine triphosphate and high-mobility group protein 1, activate Toll-like receptor-nuclear factor-κB signaling and NLRP3 inflammasome pathways, which act as major molecular drivers for initiating and amplifying the inflammatory cascade. Accordingly, targeting upstream components of innate immune signaling has shown preclinical potential to reverse hyperalgesia and central sensitization, thereby providing a new direction for the development of next-generation disease-modifying therapies. This review elucidates the central roles of innate immune signaling pathways in the initiation, maintenance, and chronification of migraine-associated neuroinflammation, and discusses recent advances and current challenges in the translational development of therapeutic strategies targeting these pathways, aiming to provide new insights into the immunopathological mechanisms of migraine and to facilitate the development of disease-modifying treatment approaches.