Pathological manifestation of autoimmune myocarditis is detected prior to glomerulonephritis in a murine model of lupus nephritis

• Published in: Lupus 2020-11, Vol.29 (13), p.1790-1799
• Main Authors: Young, Nicholas A, Jablonski, Kyle, Schwarz, Emmy, Okafor, Ifeoma, Hampton, Jeffrey, Valiente, Giancarlo R, Henry, Caitlin, Harb, Peter, Barger, Jessica, Bratasz, Anna, Kalyanasundaram, Anuradha, Ardoin, Stacy P, Jarjour, Wael N
• Format: Article
• Language: English
• Subjects: Animal models; CD4 antigen; CD8 antigen; Cytokines; Echocardiography; Edema; Fibrosis; Glomerulonephritis; Heart diseases; Histopathology; Interleukin 10; Interleukin 17; Interleukin 2; Interleukin 6; Lupus; Lupus nephritis; Lymphocytes T; Magnetic resonance imaging; Mapping; Myocarditis; Myocardium; Nephritis; Renal failure; Tumor necrosis factor-α; Urea; Ventricle
• ISSN: 0961-2033; 1477-0962
• DOI: 10.1177/0961203320948959

Objective Since enhanced cardiac magnetic resonance imaging (cMRI) signals have been associated with lupus disease activity in humans prior to renal failure and novel, cardiac-focused therapeutic strategies could be investigated with an associated animal model, autoimmune myocarditis was characterized in murine lupus nephritis (NZM2410). Methods Weekly blood urea nitrogen (BUN) levels and weights were recorded. Cardiac function was assessed by echocardiogram. Myocardial edema was measured with quantitative T2 cMRI mapping. Endpoint serum and cardiac tissue were collected for histopathological analysis and cytokine measurements. Results Despite showing no signs of significant renal disease, mice displayed evidence of myocarditis and fibrosis histologically at 30–35 weeks. Moreover, T2 cMRI mapping displayed robust signals and analysis of sagittal heart sections showed significant myocardium thickening. Cytokine expression levels of IL-2, IL-10, TNF-α, CXCL1, and IL-6 were significantly enhanced in serum. Echocardiograms demonstrated significantly increased ventricular diameters and reduced ejection fractions, while immunohistochemical staining identified CD4+ and CD8+ T cells, and IL-17 in cardiac infiltrates. Human lupus cardiac tissue showed similar histopathology with enhanced infiltrates by H&E, fibrosis, and CD4+ detection. Conclusions Histopathology, functional abnormalities, and enhanced cMRI signals indicative of myocarditis are detected in NZM2410 mice without glomerulonephritis, which supports the primary pathological role of autoimmune-mediated, cardiac-targeted inflammation in lupus.