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A small molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration
Atsuhiko Ichimura1, Sachiko Matsumoto, Shinobu Suzuki
1Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, 980-8575, Japan.
Objective:
Macrophage (Mϕ) migration rests on the adhesion/detachment between Mϕ surface components and extracellular matrixes, and the contribution of numerous inflammatory disorders. Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, influences Mϕ motility through an action distinct from its classical modulation of the plasmin-based fibrinolytic process. We rely here on a small molecule PAI-1 inhibitor (TM5275) to investigate the role of PAI-1 in Mϕ migration in the pathogenesis of renal injury.
Approach And Results:
Mϕ migration was inhibited both in vitro and in vivo by TM5275. It was also reduced in T-cell-deficient nude mice, but not in PAI-1-deficient mice. Mϕ migration hinged on the interaction of PAI-1 with low-density lipoprotein receptor-related protein, an interaction prevented by TM5275, but not with vitronectin, urokinase-type plasminogen activator, or tissue-type plasminogen activator. Fed to rats with anti-Thy-1-induced nephritis, TM5275 significantly decreased Mϕ accumulation and ameliorated the progression of renal injury.
Conclusions:
These findings suggest that a small molecule PAI-1 inhibitor represents a novel class of anti-inflammatory agents targeting Mϕ migration by the inhibition of the interaction of PAI-1 with low-density lipoprotein receptor-related protein.
Insights
A novel small molecule inhibitor targeting Plasminogen activator inhibitor-1 (PAI-1) effectively reduced macrophage migration in vitro and in vivo. This PAI-1 inhibitor shows promise for treating inflammatory kidney diseases.
Area of Science:
- Immunology
- Molecular Biology
- Nephrology
Background:
- Macrophage migration is crucial in inflammatory disorders and relies on cell-matrix interactions.
- Plasminogen activator inhibitor-1 (PAI-1) influences macrophage motility independently of fibrinolysis.
- The role of PAI-1 in renal injury pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the role of PAI-1 in macrophage migration during renal injury.
- To evaluate the efficacy of a small molecule PAI-1 inhibitor, TM5275, in modulating macrophage migration and renal pathogenesis.
Main Methods:
- Utilized a small molecule PAI-1 inhibitor (TM5275) in in vitro and in vivo models.
- Assessed macrophage migration in T-cell-deficient and PAI-1-deficient mice.
- Investigated the interaction of PAI-1 with its receptors.
- Administered TM5275 to rats with anti-Thy-1-induced nephritis.
Main Results:
- TM5275 inhibited macrophage migration both in vitro and in vivo.
- Macrophage migration reduction was dependent on PAI-1, not T-cells.
- TM5275 blocked the PAI-1 interaction with low-density lipoprotein receptor-related protein (LRP).
- TM5275 treatment ameliorated renal injury progression in a rat nephritis model by decreasing macrophage accumulation.
Conclusions:
- A small molecule PAI-1 inhibitor, TM5275, effectively targets macrophage migration.
- Inhibition of the PAI-1/LRP interaction is a key mechanism of TM5275's anti-inflammatory action.
- PAI-1 inhibition represents a novel therapeutic strategy for inflammatory renal diseases.
