Interferon stimulated genes mark pathogenic cells of the emergency myelopoietic response to sterile tissue injury in mice and humans

Sterile tissue injury recruits myeloid cells (neutrophils and monocytes) from the bone marrow by stimulating a process known as emergency myelopoiesis. It is commonly assumed that myeloid cells activate proinflammatory signaling pathways within the injured tissue after sensing innate immune-activating molecules in the local microenvironment. Here, we show that pathogenic innate immune signaling in myeloid cells begins far from the site of injury, at their origins in the bone marrow. Using myocardial infarction (MI) as a model of sterile injury, we profiled single cell transcriptomes of >50,000 myeloid cells and found evidence of type I interferon signaling characterized by expression of interferon stimulated genes (ISGs) in a subset of neutrophils and monocytes in the heart, blood, and bone marrow after MI. We validated the findings in humans by quantifying ISG-expression in myeloid cells of patients presenting with acute MI, which revealed ISG levels far exceed that of healthy subjects and are comparable to patients with the interferon-associated autoimmune disease, systemic lupus erythematous. The identification of remote innate immune education raises important questions about how distant tissue injury activates interferon signaling in the hematopoietic compartment. Clinically, our data provide a strategy for quantifying pathogenic subsets of emergency myelopoietic cells in the blood as a biomarker that may identify patients who have disproportionately worse outcomes or who may benefit from immune modulatory therapy after acute MI.