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The bm12 Inducible Model of Systemic Lupus Erythematosus SLE in C57BL/6 Mice
Published on: November 1, 2015
A Novel Preclinical Murine Model of Systemic Lupus Erythematosus-Like Cardiovascular Disease
Marice K McCrorey1, Kennedy P Hawkins1, Marharyta Semenikhina1
1Medical University of South Carolina, Charleston.
Insights
This study developed a new preclinical model for systemic lupus erythematosus (SLE)-like cardiovascular disease (CVD) in mice. Resiquimod (R848) treatment accelerated SLE, revealing sex-dependent cardiac and organ damage, crucial for understanding SLE-related CVD.
Area of Science:
- Immunology
- Cardiovascular Disease
- Preclinical Models
Background:
- Systemic lupus erythematosus (SLE) disproportionately affects women, increasing their risk for cardiovascular disease (CVD).
- Existing preclinical models lack comprehensive characterization of SLE-induced cardiac and vascular dysfunction.
- Toll-like receptor (TLR) 7/8 agonists, like resiquimod (R848), are implicated in SLE pathogenesis.
Purpose of the Study:
- To establish a novel preclinical model of SLE-like CVD using R848 in SLE-prone mice.
- To investigate the sex-dependent effects of R848 on cardiac and systemic pathophysiology.
- To analyze endothelial activation and end-organ damage in response to accelerated SLE.
Main Methods:
- Female and male B6.Nba2 mice, prone to SLE, were topically treated with R848 or acetone twice weekly for four weeks.
- Echocardiography was performed at baseline, 4, and 16 weeks to assess cardiac function.
- Tissue analysis included histology, immunofluorescence, qPCR, and ELISA to evaluate organ damage and molecular markers.
Main Results:
- R848 treatment induced SLE-like serological markers (anti-Smith antibodies, IgG complexes) and spleen enlargement in both sexes.
- Female mice showed significant cardiac and renal enlargement, left ventricular wall thickening, reduced ejection fraction, and increased cardiac/renal fibrosis.
- Both sexes exhibited elevated soluble adhesion molecules (sVCAM-1, sICAM-1), indicating systemic endothelial activation.
Conclusions:
- R848 treatment in B6.Nba2 mice provides a robust preclinical model for studying SLE-like CVD.
- The model effectively recapitulates sex-dependent differences in SLE-associated cardiovascular and organ damage.
- This model facilitates research into the pathophysiological mechanisms underlying SLE-related CVD in women.
Objective:
Systemic lupus erythematosus (SLE) affects nine women to every man worldwide, and these patients are at greater risk for cardiovascular disease (CVD) morbidity and mortality. Clinical studies have demonstrated that patients with SLE are more likely to develop CVD, including cardiac and vascular dysfunction. Although many preclinical models of SLE are available, including treatment with Toll-like receptor (TLR) 7/8 agonists, a consistent preclinical model of SLE-like CVD with systemic, cardiac, renal, and cerebral endothelial activation and cardiac dysfunction has yet to be described. Here, we hypothesize that acceleration of SLE with the TLR7/8 agonist resiquimod (R848) will promote cardiac and endothelial activation with subsequent end-stage organ damage in the SLE-prone B6.Nba2 mouse model.
Methods:
Female and male SLE-prone B6.Nba2 mice were treated with R848 or acetone, administered topically twice weekly over a four-week period, to accelerate the development of SLE-like pathophysiology. Echocardiography was performed at baseline, 4 weeks, and 16 weeks. At 16 weeks, tissues were harvested, weighed, and analyzed by histology, immunofluorescence, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assays.
Results:
We found that female R848-treated mice had increased serum anti-Smith and immunoglobulin G complex deposition in the kidney, heart, and brain consistent with SLE-like etiology. Tissue analysis revealed significant enlargement of the spleen in both female and male R848-treated mice, with only cardiac and renal enlargement in females compared to their respective controls. Echocardiographic imaging revealed left ventricular wall thickening by 4 weeks that was followed by a progressive increase in left ventricular internal diameters and subsequent decrease in ejection fraction over the 16-week time course in female mice. We found that circulating levels of soluble vascular adhesion molecule-1 and soluble intracellular adhesion molecule-1 were increased in both female and male R848-treated mice, whereas cardiac and renal fibrosis were significantly increased in only female R848-treated mice.
Conclusion:
Our data demonstrate that R848 treatment of SLE-prone B6.Nba2 mice is a novel preclinical model to study the sex-dependent pathophysiologic mechanisms of SLE-like CVD.
