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Spatially clustered type I interferon responses at injury borderzones
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Journal Article
Spatially clustered type I interferon responses at injury borderzones
2024
Overview
Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone
1
,
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 survival
3
. 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.
Cardiomyocytes are the dominant initiators of a type I interferon response in the infarct borderzone.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/39
/ 38/91
/ 45/41
/ 64/110
/ 64/60
/ 96/21
/ 96/35
/ 96/63
/ 96/95
/ Animals
/ Cells
/ Dendritic Cells - immunology
/ Endothelial Cells - metabolism
/ Female
/ Genes
/ Humanities and Social Sciences
/ Humans
/ Interferon regulatory factor 3
/ Interferon Regulatory Factor-3 - antagonists & inhibitors
/ Interferon Regulatory Factor-3 - deficiency
/ Interferon Regulatory Factor-3 - metabolism
/ Interferon Type I - immunology
/ Interferon Type I - metabolism
/ Ischemia
/ Male
/ Mice
/ Myocardial Infarction - immunology
/ Myocardial Infarction - metabolism
/ Myocardial Infarction - pathology
/ Myocytes, Cardiac - metabolism
/ Myocytes, Cardiac - pathology
/ Receptors, CCR2 - deficiency
/ Receptors, CCR2 - metabolism
/ Rupture
/ Science
