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Updated: Dec 15, 2025
An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in macrophage inflammation and
Laura Senatus1, Raquel López-Díez1, Lander Egaña-Gorroño1
1Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
Abstract:
Despite advances in lipid-lowering therapies, people with diabetes continue to experience more limited cardiovascular benefits. In diabetes, hyperglycemia sustains inflammation and preempts vascular repair. We tested the hypothesis that the receptor for advanced glycation end-products (RAGE) contributes to these maladaptive processes. We report that transplantation of aortic arches from diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene encoding RAGE) versus WT diabetic recipient mice accelerated regression of atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms principally to the recipient macrophages and linked RAGE to interferon signaling. Specifically, deletion of Ager in the regressing diabetic plaques downregulated interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry studies colocalized IRF7 and macrophages in both murine and human atherosclerotic plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene expression and regulated a host of genes linked to cholesterol efflux and homeostasis. Collectively, this work adds a new dimension to the immunometabolic sphere of perturbations that impair regression of established diabetic atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular repair in diabetes.
Insights
Targeting the receptor for advanced glycation end-products (RAGE) and interferon regulatory factor 7 (IRF7) may improve cardiovascular health in diabetes. This study reveals their role in impairing atherosclerosis regression in diabetic mice.
Area of Science:
- Immunometabolism
- Vascular Biology
- Diabetes Complications
Background:
- Cardiovascular disease remains a significant concern for diabetic patients, with limited benefits from current lipid-lowering therapies.
- Hyperglycemia in diabetes promotes vascular inflammation and hinders repair mechanisms.
- The receptor for advanced glycation end-products (RAGE) is implicated in these detrimental processes.
Purpose of the Study:
- To investigate the role of RAGE in the impaired regression of atherosclerosis in diabetes.
- To elucidate the molecular mechanisms linking RAGE to inflammation and vascular repair in diabetic atherosclerosis.
Main Methods:
- Transplantation of aortic arches from diabetic mice into RAGE-deficient (Ager-/-) versus wild-type (WT) diabetic recipient mice.
- RNA sequencing of plaque macrophages to identify RAGE-dependent pathways.
- Immunohistochemistry to localize IRF7 and macrophages in murine and human plaques.
- In vitro studies using bone marrow-derived macrophages (BMDMs) to assess RAGE ligand effects on IRF7 and inflammatory gene expression.
Main Results:
- Deletion of RAGE in diabetic recipient mice accelerated atherosclerosis regression.
- RAGE deficiency downregulated interferon regulatory factor 7 (IRF7) in plaque macrophages.
- RAGE ligands upregulated IRF7 in BMDMs.
- IRF7 knockdown in cholesterol-loaded BMDMs shifted gene expression from pro-inflammatory to anti-inflammatory profiles, impacting cholesterol homeostasis.
Conclusions:
- RAGE and IRF7 play a critical role in the immunometabolic dysregulation that impedes atherosclerosis regression in diabetes.
- Targeting the RAGE-IRF7 axis presents a potential therapeutic strategy to promote vascular repair and improve cardiovascular outcomes in diabetic patients.
