Legumain Restrains Granuloma Formation by Inhibiting mTORC1/STAT1-Mediated M1 Macrophage Polarization in Sarcoidosis.
Summary
Legumain is upregulated in sarcoid-like granulomas and restrains M1 polarization via integrin αvβ3-dependent inhibition of mTORC1/STAT1 signaling. Intratracheal lipid nanoparticles delivering Lgmn plasmid reduced granuloma burden in two mouse models, nominating LGMN supplementation as a therapeutic strategy.
Key Findings
- LGMN expression is increased in macrophages within sarcoid-like granulomas.
- Lgmn knockout exacerbates granulomatous inflammation with enhanced M1 polarization in P. acnes-induced mice.
- LGMN binds integrin αvβ3 to inhibit mTORC1/STAT1 signaling, and intratracheal LNP-Lgmn therapy reduces granuloma formation.
Clinical Implications
LGMN-based therapies, including airway-delivered gene augmentation, could offer an alternative for refractory sarcoidosis; biomarkers of M1 polarization and mTORC1/STAT1 activity may guide patient selection.
Why It Matters
This study pinpoints a macrophage-intrinsic checkpoint of granuloma biology and demonstrates a tractable gene-delivery approach, bridging mechanistic insight with a translational therapeutic modality for sarcoidosis.
Limitations
- Human sample validation and safety/pharmacokinetics of airway gene delivery were not addressed
- Quantitative dosing-response and durability of LNP-mediated gene expression require further study
Future Directions
Advance LGMN augmentation to large-animal safety studies; explore small-molecule or peptide agonists; develop companion diagnostics of macrophage polarization to stratify sarcoidosis patients.
Study Information
- Study Type
- Basic/mechanistic study
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic and therapeutic proof-of-concept in mouse models
- Study Design
- OTHER