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Spatially clustered type I interferon responses at injury borderzones
V K Ninh1, D M Calcagno2, J D Yu2
1Division of Cardiology and Cardiovascular Institute, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Insights
Cardiomyocytes, not immune cells, initiate sterile inflammation after heart attack by releasing DNA and triggering interferon responses. This response worsens heart damage and rupture risk, suggesting IRF3 inhibition as a potential therapy.
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.
Abstract:
Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.
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