Cardiomyocytes can activate the type I interferon (IFN) response in the infarct border zone after myocardial infarction (MI), whereas inhibition of this IFN activation prevents the loss of activated fibroblasts in the border zone and reduces the risk of ventricular rupture, according to a new study in Nature. These findings suggest that the type I IFN pathway, in addition to its well-established role in antiviral responses, is also involved in cardiac injury.

In the present study, spatial transcriptomics analysis of infarcted mouse hearts revealed the presence of IFN-induced cells (IFNICs) that were spatially localized to the border zone of the infarct. Similarly, colonies of IFNICs were present in samples of human hearts after acute MI. Sequencing-based spatial transcriptomic analysis and an image-based RNA profiling technique performed in cell type-specific Irf3-knockout mice after MI showed that cardiomyocytes were the main initiators of the type I IFN response. This surprising finding led to the hypothesis that the presence of these IFNIC colonies at the infarct border zone was the result of mechanical stress on the surviving cardiomyocytes at the edge of the border zone, which can cause transient nuclear rupture. To test this theory, the investigators induced trauma to the mid-ventricle in mice by inserting and removing a fine needle and found evidence of nuclear rupture and extranuclear DNA in load-bearing cells (cardiomyocytes and fibroblasts) in the border zone of the infarct. Detection of spillage of nuclear material into the cytoplasm of cardiomyocytes suggests that the IFN pathway is activated by nucleic acid sensing. The investigators subsequently showed that treating human cardiac fibroblasts in vitro with IFNβ suppressed contractility and reduced the expression of extracellular matrix proteins, highlighting a mechanism through which type I IFN activation can increase the risk of ventricular rupture. Indeed, mice lacking IFNICs were protected from ventricular rupture and had higher survival than wild-type mice.