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Fibroblast reprogramming in the dura mater of NTG-induced migraine-related chronic hypersensitivity model drives monocyte infiltration via Angptl1-dependent stromal signaling
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Fibroblast reprogramming in the dura mater of NTG-induced migraine-related chronic hypersensitivity model drives monocyte infiltration via Angptl1-dependent stromal signaling
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Journal Article
Fibroblast reprogramming in the dura mater of NTG-induced migraine-related chronic hypersensitivity model drives monocyte infiltration via Angptl1-dependent stromal signaling
2025
Overview
Background
Migraine, characterized by recurrent episodes of severe headache, remains mechanistically enigmatic. While traditional theories emphasize trigeminovascular activation, the role of meningeal stromal-immune crosstalk in disease chronicity is poorly understood.
Methods
A migraine-related chronic hypersensitivity model was utilized via intermittent intraperitoneal nitroglycerin (NTG, 10 mg/kg, every other day for 9 days) and peripheral mechanical hypersensitivity was assessed using von Frey filaments. Single-cell RNA sequencing (scRNA-seq) was performed on dura tissues to construct a cellular atlas of NTG-induced remodeling. These data were then integrated with migraine genome-wide association study (GWAS) risk genes, cell-cell interaction networks, and transcriptional regulation analysis to dissect NTG-driven meningeal remodeling.
Results
The NTG-induced migraine-related chronic hypersensitivity model demonstrated sustained mechanical allodynia, as evidenced by significantly decreased paw withdrawal thresholds (
p
< 0.0001). Single-cell profiling of the dura mater revealed a 2.4-fold expansion of a pro-inflammatory fibroblast subpopulation (Fibro_c5: 1.9% in Vehicle vs. 4.6% in NTG group), which exhibited marked activation of TNF-α/NF-κB signaling pathways (normalized enrichment score [NES] = 1.83). Concomitantly, we observed an 82% increase in meningeal monocytes (5.7–10.4%) that showed preferential interaction with Fibro_c5 fibroblasts through Angptl1-mediated stromal-immune crosstalk (log2 fold change = 1.41). Regulatory network analysis identified Mafk as the upstream transcriptional regulator orchestrating Angptl1 expression in this pathological communication axis.
Conclusion
Our study reveals that NTG reprograms meningeal fibroblasts to expand a pro-inflammatory fibroblast subtype, which drives migraine-related chronic hypersensitivity through TNF-α/NF-κB signaling and Angptl1-mediated monocyte crosstalk. The identified Mafk-Angptl1 axis presents a potential therapeutic target, though human validation remains essential.
Publisher
Springer Milan,Springer Nature B.V,BMC
Subject
2025 Early Career Research Mentorship Program
/ Angiopoietin-like Proteins - metabolism
/ Animals
/ Cellular Reprogramming - physiology
/ Dura
/ Genome-wide association studies
/ Headache
/ Hyperalgesia - chemically induced
/ Male
/ Medicine
/ Mice
/ Migraine
/ Migraine Disorders - chemically induced
/ Migraine Disorders - immunology
/ Migraine Disorders - metabolism
/ Migraine-related chronic hypersensitivity
