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Updated: Nov 10, 2025
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
RAGE signaling antagonist suppresses mouse macrophage foam cell formation
Nontaphat Leerach1, Seiichi Munesue1, Ai Harashima1
1Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
Abstract:
The engagement of the receptor for advanced glycation end-products (receptor for AGEs, RAGE) with diverse ligands could elicit chronic vascular inflammation, such as atherosclerosis. Binding of cytoplasmic tail RAGE (ctRAGE) to diaphanous-related formin 1 (Diaph1) is known to yield RAGE intracellular signal transduction and subsequent cellular responses. However, the effectiveness of an inhibitor of the ctRAGE/Diaph1 interaction in attenuating the development of atherosclerosis is unclear. In this study, using macrophages from Ager+/+ and Ager-/- mice, we validated the effects of an inhibitor on AGEs-RAGE-induced foam cell formation. The inhibitor significantly suppressed AGEs-RAGE-evoked Rac1 activity, cell invasion, and uptake of oxidized low-density lipoprotein, as well as AGEs-induced NF-κB activation and upregulation of proinflammatory gene expression. Moreover, expression of Il-10, an anti-inflammatory gene, was restored by this antagonist. These findings suggest that the RAGE-Diaph1 inhibitor could be a potential therapeutic drug against RAGE-related diseases, such as chronic inflammation and atherosclerosis.
Insights
A novel inhibitor targeting the receptor for advanced glycation end-products (RAGE) and Diaphanous-related formin 1 (Diaph1) interaction suppressed atherosclerosis development. This RAGE-Diaph1 inhibitor shows potential for treating chronic inflammatory diseases.
Area of Science:
- Vascular Biology
- Immunology
- Pharmacology
Background:
- Receptor for advanced glycation end-products (RAGE) engagement promotes chronic vascular inflammation, including atherosclerosis.
- The interaction between cytoplasmic tail RAGE (ctRAGE) and diaphanous-related formin 1 (Diaph1) mediates RAGE intracellular signaling.
- The therapeutic potential of inhibiting the ctRAGE/Diaph1 interaction against atherosclerosis remains largely unexplored.
Purpose of the Study:
- To investigate the efficacy of a ctRAGE/Diaph1 inhibitor in preventing atherosclerosis.
- To evaluate the inhibitor's effects on AGEs-RAGE-induced macrophage responses.
Main Methods:
- Utilized macrophages from wild-type (Ager+/+) and knockout (Ager-/-) mice.
- Assessed the impact of the ctRAGE/Diaph1 inhibitor on AGEs-RAGE-induced foam cell formation.
- Measured Rac1 activity, cell invasion, oxidized low-density lipoprotein uptake, NF-κB activation, and gene expression.
Main Results:
- The inhibitor significantly reduced AGEs-RAGE-induced Rac1 activity, cell invasion, and oxidized low-density lipoprotein uptake.
- AGEs-induced NF-κB activation and pro-inflammatory gene expression were suppressed by the inhibitor.
- The antagonist treatment restored the expression of the anti-inflammatory gene Il-10.
Conclusions:
- The ctRAGE/Diaph1 inhibitor effectively attenuates key pathways involved in atherosclerosis development.
- This inhibitor demonstrates promise as a therapeutic agent for RAGE-related inflammatory diseases like atherosclerosis.
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