Nat. Med. 23, 1481–1487 (2017)

The molecular drivers of myocardial infarction (MI)-driven inflammation remain unclear. In Nature Medicine, King et al. show that uptake of cellular debris by cardiac macrophages after ischemic cell death activates the production of type I interferons. Activation of the transcription factor IRF3 and induction of the cytokine- and chemokine-encoding genes Ifnb1 and Cxcl10 are detected 4 d after MI in wild-type mice but not in mice deficient in the adaptor STING or the DNA sensor cGAS. Uptake of dying cardiomyocytes by F4/80hiLy6Clo phagocytic macrophages triggers the IRF3-dependent recruitment of blood F4/80loLy6Chi pro-inflammatory monocytes that amplify the inflammatory response. Irf3–/– mice and mice deficient in the interferon receptor IFNAR are protected from death and show fewer signs of heart failure after MI. Treatment with IFNAR-neutralizing antibodies at 12 and 48 h after MI improves ventricular size, contractile function and survival in mice.