IL-1-Activated Inflammatory Cardiac Fibroblasts Exacerbate Acute Coxsackievirus B3 Myocarditis

Area of Science:

• Cardiology
• Immunology
• Molecular Biology

Background:

• Acute viral myocarditis is a severe heart condition often triggered by viral infections.
• Inflammatory fibroblasts (IFs) play a role in cardiac inflammation, but their specific contribution to viral myocarditis is not fully understood.

Purpose of the Study:

• To investigate the role of inflammatory fibroblasts (IFs) in the pathogenesis of acute viral myocarditis.
• To identify key signaling pathways that activate IFs during viral myocarditis.
• To explore the therapeutic potential of targeting fibroblast-specific signaling in myocarditis.

Main Methods:

• Utilized CCL2-mCherry reporter mice to track IF kinetics during coxsackievirus B3 (CVB3) infection.
• Generated PDGFRα^creIL1r1^fl/fl mice to specifically delete IL-1 receptor signaling in fibroblasts.
• Analyzed cardiac inflammation, immune cell infiltration (monocytes, T cells, NK cells), and viral clearance in mouse models.
• Examined endomyocardial biopsies from human patients to confirm the presence of IFs.

Main Results:

• IF activity peaked on day 3 of CVB3-induced myocarditis.
• Activated IFs produced Th1, Th2, and Th17 chemokines, not profibrotic genes.
• Interleukin-1 beta (IL-1β) was identified as a potent activator of IFs.
• Targeted deletion of IL-1 signaling in fibroblasts reduced cardiac inflammation by 45% without impairing viral clearance.
• IFs were confirmed in human myocarditis biopsies.

Conclusions:

• Fibroblast-specific IL-1 signaling is a critical driver of cardiac inflammation in acute viral myocarditis.
• Targeting fibroblast IL-1 signaling represents a promising therapeutic strategy for myocarditis.
• IFs contribute to disease pathogenesis by orchestrating an inflammatory chemokine response.