Spatially clustered type I interferon responses at injury borderzones

Area of Science:

• Cardiovascular Biology
• Innate Immunology
• Molecular Cardiology

Background:

• Sterile inflammation post-myocardial infarction (MI) was attributed to myeloid cells and cellular debris.
• The precise cellular origin and mechanisms of the early innate immune response in the infarct border zone remain incompletely understood.

Purpose of the Study:

• To identify the primary cell type initiating the type I interferon response in the infarct border zone after myocardial infarction.
• To elucidate the molecular mechanisms and downstream consequences of this cardiomyocyte-derived immune activation.

Main Methods:

• Spatial transcriptomics analysis in mouse and human hearts post-MI.
• Genetic manipulation using cardiomyocyte-specific Irf3 deletion and other cell-type-specific knockouts.
• Assessment of fibroblast function, cardiac remodeling, and ventricular rupture in vivo.

Main Results:

• Cardiomyocytes, not myeloid cells, are the dominant initiators of a type I interferon response in the infarct border zone.
• Myocardial infarction induces interferon-induced cells (IFNICs) originating from cardiomyocyte nuclear rupture and chromosomal DNA release.
• Cardiomyocyte-specific IRF3 activation is essential for IFNIC formation; its absence protects against rupture and improves survival.
• Interferons impair border zone fibroblast function, promoting pathological remodeling and increasing susceptibility to ventricular rupture.

Conclusions:

• A novel pathological niche exists in the infarct border zone, characterized by a cardiomyocyte-initiated innate immune response.
• Targeting IRF3 activation specifically in non-immune cells offers a potential therapeutic strategy to limit ischaemic cardiomyopathy and prevent rupture without broad immunosuppression.