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Updated: Sep 28, 2025
Murine Flexor Tendon Injury and Repair Surgery
Published on: September 19, 2016
Disulfiram Suppressed Peritendinous Fibrosis Through Inhibiting Macrophage Accumulation and Its Pro-inflammatory
Qi Zhou1,2, Wei Wang1, Fujun Yang2,3
1Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
The communication between macrophages and tendon cells plays a critical role in regulating the tendon-healing process. However, the potential mechanisms through which macrophages can control peritendinous fibrosis are unknown. Our data showed a strong pro-inflammatory phenotype of macrophages after a mouse tendon-bone injury. Moreover, by using a small-molecule compound library, we identified an aldehyde dehydrogenase inhibitor, disulfiram (DSF), which can significantly promote the transition of macrophage from M1 to M2 phenotype and decrease macrophage pro-inflammatory phenotype. Mechanistically, DSF targets gasdermin D (GSDMD) to attenuate macrophage cell pyroptosis, interleukin-1β, and high mobility group box 1 protein release. These pro-inflammatory cytokines and damage-associated molecular patterns are essential for regulating tenocyte and fibroblast proliferation, migration, and fibrotic activity. Deficiency or inhibition of GSDMD significantly suppressed peritendinous fibrosis formation around the injured tendon and was accompanied by increased regenerated bone and fibrocartilage compared with the wild-type littermates. Collectively, these findings reveal a novel pathway of GSDMD-dependent macrophage cell pyroptosis in remodeling fibrogenesis in tendon-bone injury. Thus, GSDMD may represent a potential therapeutic target in tendon-bone healing.
Insights
Disulfiram (DSF) targets gasdermin D (GSDMD) to reduce macrophage pyroptosis, thereby decreasing tendon fibrosis after injury. Inhibiting GSDMD promotes tendon healing and tissue regeneration, suggesting GSDMD as a therapeutic target.
Area of Science:
- Immunology
- Regenerative Medicine
- Orthopedic Surgery
Background:
- Macrophage communication with tendon cells is crucial for tendon healing.
- Mechanisms by which macrophages influence peritendinous fibrosis remain unclear.
- Macrophage pro-inflammatory phenotypes are observed following tendon-bone injury.
Purpose of the Study:
- To investigate the role of macrophage pyroptosis in peritendinous fibrosis.
- To identify therapeutic targets for improving tendon-bone healing.
Main Methods:
- Utilized a small-molecule compound library to screen for modulators of macrophage phenotype.
- Investigated the effect of disulfiram (DSF) on macrophage polarization and pyroptosis.
- Examined the role of gasdermin D (GSDMD) in a mouse model of tendon-bone injury.
Main Results:
- Disulfiram (DSF) promoted macrophage transition from M1 to M2 phenotype, reducing pro-inflammatory markers.
- DSF inhibited macrophage pyroptosis by targeting gasdermin D (GSDMD), decreasing release of IL-1β and HMGB1.
- GSDMD deficiency or inhibition significantly reduced peritendinous fibrosis and enhanced bone and fibrocartilage regeneration.
Conclusions:
- Macrophage pyroptosis, mediated by GSDMD, is a key pathway in fibrogenesis following tendon-bone injury.
- Targeting GSDMD presents a novel therapeutic strategy for enhancing tendon-bone healing.
- DSF's ability to modulate macrophage phenotype and pyroptosis offers potential for treating fibrotic conditions in tendon injuries.
