Meningeal mast cells and macrophages in migraine: an underexplored neuroimmune interface and candidate therapeutic target

Migraine prevention has advanced through therapies targeting calcitonin gene-related peptide (CGRP) or its receptor, but incomplete clinical responses remain multifactorial and cannot be attributed to meningeal mast-cell activation without direct evidence. Experimental work demonstrates interactions among dural mast cells, macrophages and trigeminal afferents. Recent receptor-expression analyses suggest MRGPRX2 as a candidate convergence point for substance P and PACAP in human dural mast cells, although the relevant dataset is small and does not demonstrate receptor-mediated responses during migraine. We distinguish ligand-dependent downstream signalling from hypothetical responses to ATP or other agonists after neuropeptide blockade; the magnitude of any residual immune response is unknown. Cortical spreading depression (CSD) can evoke meningeal immune-cell changes in rodents, but fremanezumab-insensitive vascular dilation and extravasation do not establish persistent immune activation, nociception or treatment resistance. Hormonal and metabolic influences are considered potential modifiers, and lymphatic alterations are discussed only as an exploratory secondary hypothesis. Negative and inconsistent human evidence, including peripheral mediator measurements and historical antihistamine studies, argues against immediate systemic mast-cell depletion or imatinib repurposing. We propose a staged programme of clinical phenotyping, receptor-specific target engagement and mechanistic discrimination of immune, vascular and afferent endpoints before low-risk clinical proof of concept. This Perspective advances a falsifiable candidate mechanism rather than a demonstrated explanation of anti-CGRP/CGRP-receptor non-response.