Meningeal lymphatic vessel dysfunction driven by CGRP signaling causes migraine-like pain in mice

Abstract

Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.

Figure 1. CGRP signaling mediates the functional interplay between MLVs and migraine.

(A) CGRP-expressing trigeminal nerve roots are in close proximity to CGRP receptor–expressing MLVs. (B) In deep cervical lymph nodes (DCLNs), MAdCAM1-expressing lymphatic endothelial cells (LECs) interact with CD4⁺ T cells to promote pathologic lymphatic vessel remodeling via CGRP signaling. (C) Decreased permeability in MLVs reduces CSF outflow to DCLNs.