Spatially clustered type I interferon responses at injury borderzones.

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.

Single-cell and spatial transcriptomics of the infarcted heart define the dynamic onset of the border zone in response to mechanical destabilization.

The border zone (BZ) of the infarcted heart is a geographically complex and biologically enigmatic interface separating poorly perfused infarct zones (IZs) from remote zones (RZs). The cellular and molecular mechanisms of myocardial BZs are not well understood because microdissection inevitably combines them with uncontrolled amounts of RZs and IZs. Here, we use single-cell/nucleus RNA sequencing, spatial transcriptomics and multiplexed RNA fluorescence in situ hybridization to redefine the BZ based on cardiomyocyte transcriptomes. BZ1 (Nppa + Xirp2 -) forms a hundreds-of-micrometer-thick layer of morphologically intact cells adjacent to RZs that are detectable within an hour of injury. Meanwhile, BZ2 (Nppa + Xirp2 +) forms a near-single-cell-thick layer of morphologically distorted cardiomyocytes at the IZ edge that colocalize with matricellular protein-expressing myofibroblasts and express predominantly mechanotransduction genes. Surprisingly, mechanical injury alone is sufficient to induce BZ genes. We propose a 'loss of neighbor' hypothesis to explain how ischemic cell death mechanically destabilizes the BZ to induce its transcriptional response.