Methotrexate loaded extracellular vesicles attenuate periodontitis by suppressing ACSL1 and promoting anti-inflammatory macrophage

  • Mol Immunol. 2025 Jun:182:83-95. doi: 10.1016/j.molimm.2025.04.005.
Zhi Liu  1 ,  Jianhua Yang  2 ,  Guodong Tan  3 ,  Yuanyuan Shi  4 ,  Dihao Tao  2 ,  Wenzhe Wang  2 ,  Bei Li  2 ,  Fang Jin  5 ,  Xiaoning He  6
Affiliations
  • 1. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
  • 2. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
  • 3. Air Force Medical Center, The Fourth Military Medical University, Beijing 100142, China.
  • 4. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
  • 5. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: [email protected].
PMID: 40245705 DOI: 10.1016/j.molimm.2025.04.005
Abstract

Macrophages are crucial immune cells in periodontal tissues, which play key roles in both the destruction and repair of associated with periodontitis. Targeted modulation of macrophage function has emerged as a potentially effective approach to influence periodontitis progression. This study investigates the effects of methotrexate-loaded extracellular vesicles (MTX-EVs) on inflammatory macrophage polarization both in vivo and in vitro. In a murine periodontitis model, MTX-EVs inhibited alveolar bone resorption, suppressed pro-inflammatory macrophage activation, and promoted anti-inflammatory macrophages. Mechanistically, MTX-EVs reduced acyl-CoA synthetase-1 (ACSL1) expression, which was elevated during inflammation. Inhibition of ACSL1 with triacsin-C in macrophages suppressed the inflammatory phenotype through the promotion of the Oxidative Phosphorylation (OXPHOS). In contrast, MTX-EVs counteracted the effects of ACSL1 overexpression on macrophage polarization and metabolism. Our findings suggest that targeting ACSL1 via MTX-EVs represents a therapeutic strategy for modulating macrophage polarization and improving periodontitis treatment outcomes.

Keywords
ACSL1; Extracellular vesicles; Macrophage; Methotrexate; Periodontitis.
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