Spatially clustered type I interferon responses at injury borderzones

Nature. 2024 Sep;633(8028):174-181. doi: 10.1038/s41586-024-07806-1. Epub 2024 Aug 28.

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.

MeSH terms

  • Animals
  • Dendritic Cells / immunology
  • Endothelial Cells / metabolism
  • Female
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / antagonists & inhibitors
  • Interferon Regulatory Factor-3 / deficiency
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I* / immunology
  • Interferon Type I* / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction* / immunology
  • Myocardial Infarction* / metabolism
  • Myocardial Infarction* / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Neutrophils / metabolism
  • Receptors, CCR2 / deficiency
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism

Substances

  • Ccr2 protein, mouse
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • IRF3 protein, human
  • Irf3 protein, mouse
  • Receptors, CCR2