Immature neutrophils in myocardial infarction: a new culprit in adverse cardiac remodeling after MI

Abstract Myocardial infarction (MI) remains a leading cause of mortality worldwide. Neutrophils are among the first immune responders to myocardial injury. Recent evidence indicates that approximately 10% of circulating neutrophils exhibited an immature phenotype in MI patients, a finding we were able to recapitulate in mice. However, functional significance of this subset remains unclear, partly due to limitations in conventional murine MI models. To address this, we analyzed neutrophil subsets in the blood of MI patients 24-48 hours post-infarction and employed a murine minimal-invasive MI model for parallel investigation. We found that immature neutrophils infiltrated the infarcted myocardium within 24h post-MI and were functionally active. Like mature granulocytes, immature neutrophils exhibited increased phagocytic activity but also elevated reactive oxygen species (ROS) production upon infarction. Administration of G-CSF after MI increased numbers of circulating and infiltrating immature neutrophils 24h after infarction, without affecting mature neutrophil levels. Furthermore, early expansion of immature neutrophils during the initial inflammatory response was associated with a reduction of ejection fraction and increased cardiac fibrosis at later stages. Our findings suggest that G-CSF facilitates the mobilization and cardiac recruitment of bone marrow-derived immature neutrophils following MI. Moreover, G-CSF-mediated expansion of immature neutrophils results in contractile dysfunction and sustained inflammation during post-infarction cardiac remodeling. Collectively, these results implicate immature neutrophils as active contributors to maladaptive remodeling and prolonged post-MI inflammation. We propose that circulating immature neutrophils can serve as an early predictive biomarker for patients at increased risk of developing severe heart failure symptoms after MI and could be used as platform for future therapies.