Spatially clustered type I interferon responses at injury borderzones [scRNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1119369 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29262105_1.fastq.gz | Fastqsanger.gz | |||
| SRR29262105_2.fastq.gz | Fastqsanger.gz | |||
| SRR29262106_1.fastq.gz | Fastqsanger.gz | |||
| SRR29262106_2.fastq.gz | Fastqsanger.gz | |||
| SRR29262107_1.fastq.gz | Fastqsanger.gz |
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Project description:Spatially clustered type I interferon responses at injury borderzones
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Project description:Sterile inflammation after myocardial infarction (MI) is classically credited to myeloid cells interacting with dead cell debris in the infarct zone (IZ). Here, we show that borderzone cardiomyocytes are the dominant initiators of a novel type I interferon (IFN) response in the infarct borderzone zone (BZ). Using spatial transcriptomics analysis of mice and humans, we find that MI induces colonies of interferon induced cells (IFNICs) expressing interferon stimulated genes (ISGs) decorating the BZ, where cardiomyocytes experience mechanical stress, nuclear rupture, and escape of chromosomal DNA. Cardiomyocyte-selective deletion of interferon regulatory factor 3 (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. IFNs blunted the protective matricellular programs and contractile function of BZ fibroblasts, and increased vulnerability to pathologic remodeling. In mice that died after MI, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival. Together, these results reveal a pathologic BZ niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of Irf3 activation in non-immune cells of the borderzone could limit ischemic cardiomyopathy while avoiding broad immunosuppression.
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Project description: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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Project description:Sterile inflammation post-myocardial infarction was thought to be driven by myeloid cells, however, we show that borderzone cardiomyocytes are the critical initators of the Type I Interferon response through spatial, single-cell, and single-nuclei transcriptomics.
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