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MMP-9 affects dural cell composition and granulocyte accumulation during neuroinflammation
Sheng-Hsiang Shen1, Hanna Gerwien2, Miriam Burmeister2
1Department of Neurology, Medical Faculty, University Hospital Muenster, Münster, Germany.
Introduction:
Matrix metalloproteinases MMP-2 and MMP-9 modulate inflammatory processes at the blood-brain barrier (BBB), but their presence and function in the dura mater remain unclear. We therefore investigated their contribution to immune regulation at this site during neuroinflammation.
Methods:
We analyzed dura mater from naïve and experimental autoimmune encephalomyelitis (EAE) mice using immunofluorescence, gelatin zymography, flow cytometry, and single-nucleus RNA sequencing (snRNA-seq). Comparisons were performed between wild-type (WT) and Mmp9-/- mice to define gelatinase expression, cellular sources, transcriptional alterations, and immune cell dynamics.
Results:
Pro- and activated-MMP-2 and MMP-9 were detectable in naïve dura, with selective upregulation of MMP-9 during EAE. Mmp9-/- mice demonstrated delayed EAE onset but more severe disease at peak. SnRNA-seq revealed that Mmp9 deficiency altered endothelial transcriptional programs, especially in venous endothelial cells, and promoted expansion of granulocyte populations with mature neutrophil signatures. Flow cytometry and immunofluorescence confirmed increased Ly6C⁺Ly6G⁺ neutrophils in Mmp9-/- dura during EAE.
Discussion:
Our findings indicate that MMP-9 regulates immune cell composition and activation within the dura during neuroinflammation. While Mmp9 deficiency delays disease onset, it enhances neutrophil accumulation and inflammatory responses at this CNS border, suggesting a previously unrecognized, potentially anti-inflammatory role for MMP-9 in the dura.
Insights
Matrix metalloproteinase-9 (MMP-9) plays a key role in regulating dura mater immunity during neuroinflammation. While its absence delays disease onset, it increases neutrophil accumulation and inflammation at the central nervous system border.
Area of Science:
- Neuroimmunology
- Mesenchymal Stem Cell Biology
- Blood-Brain Barrier Research
Background:
- Matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, are known to influence inflammatory processes at the blood-brain barrier (BBB).
- However, their precise roles and presence within the dura mater, a critical interface during neuroinflammation, remain largely uncharacterized.
Purpose of the Study:
- To investigate the contribution of MMP-2 and MMP-9 to immune regulation within the dura mater during experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation.
- To define the expression, cellular sources, and functional impact of gelatinases in the dura mater.
Main Methods:
- Analysis of dura mater from naive and EAE-induced wild-type (WT) and MMP-9 knockout (Mmp9-/-) mice.
- Techniques included immunofluorescence, gelatin zymography, flow cytometry, and single-nucleus RNA sequencing (snRNA-seq).
Main Results:
- MMP-2 and MMP-9 were detected in naive dura, with MMP-9 significantly upregulated during EAE.
- Mmp9-/- mice exhibited delayed EAE onset but more severe disease.
- MMP-9 deficiency altered endothelial cell gene expression and increased neutrophil populations in the dura mater.
Conclusions:
- MMP-9 is a key regulator of immune cell dynamics and activation in the dura mater during neuroinflammation.
- Despite delaying disease onset, MMP-9 deficiency exacerbates neutrophil infiltration and inflammation, suggesting a potentially protective role for MMP-9 in this CNS border tissue.
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