# Osteopontin promoted cardiac inflammation through increased interleukin-12 in acute myocarditis

## TL;DR

This study shows that osteopontin promotes heart inflammation in viral myocarditis by increasing interleukin-12, suggesting it could be a target for treatment.

## Contribution

The study identifies a novel mechanism by which osteopontin drives inflammation in acute viral myocarditis through macrophage-derived interleukin-12.

## Key findings

- Macrophages are the primary source of osteopontin in the heart during viral myocarditis.
- Genetic ablation of osteopontin in macrophages reduces cardiac dysfunction and immune cell infiltration.
- Pharmacological inhibition of STAT4 suppresses osteopontin expression in vivo.

## Abstract

Osteopontin (OPN) is a multifunctional glycoprotein known to play critical roles in autoimmunity and tissue repair, yet its function in acute viral myocarditis remains poorly understood. To systematically investigate the pathogenesis of viral myocarditis, this study integrated clinical observations from patients with myocarditis and four genetically distinct mouse strains following intraperitoneal inoculation with coxsackievirus B3 (CVB3). Cardiac transcriptomic profiling via RNA-seq uncovered global changes in gene expression, while quantitative RT-PCR and ELISA assays were employed to measure OPN expression levels in cardiac tissues and plasma. A macrophage-specific OPN knockout (OPN−/−) model was generated by crossing OPN flox/flox mice with Lyz2-Cre transgenic mice. In patients with myocarditis, elevated levels of plasma OPN were observed, suggesting its potential utility as a diagnostic biomarker. In murine models, cardiac OPN expression was significantly upregulated during acute viral myocarditis and exhibited a strong inverse correlation with systolic and diastolic function. Further analyses identified macrophages as the primary cellular source of OPN in the heart. Mechanistically, macrophage-derived OPN was shown to enhance the secretion of IL-12, thereby amplifying the local inflammatory response. Genetic ablation of OPN in macrophages markedly attenuated CVB3-induced cardiac dysfunction and reduced myocardial immune cell infiltration. STAT4 was demonstrated to directly bind to the promoter region of OPN and enhance its expression. Correspondingly, pharmacological inhibition of STAT4 using lisofylline significantly suppressed OPN expression in vivo. In summary, OPN functions as a crucial pro-inflammatory regulator in acute viral myocarditis and represents a promising therapeutic target for mitigating virus-induced cardiac damage.

The online version contains supplementary material available at 10.1186/s43556-025-00333-z.