A cardio-splenic-NET axis mediates acute MI and post-MI heart failure

About This Grant

Project Summary Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Despite advances in early reperfusion strategies, inflammation triggered during ischemia/reperfusion injury (IRI) contributes not only to acute myocardial damage but also to chronic adverse remodeling and the development of post-MI heart failure (HF). This project focuses on the immunopathological role of the cardio-splenic axis, particularly the early activation of plasmacytoid dendritic cells (pDCs), in orchestrating post-MI inflammation and cardiac dysfunction. Our central hypothesis is that cell-free DNA (cfDNA) released from ischemically injured myocardium, in complex with high mobility group box 1 (HMGB1), activates splenic pDCs via RAGE–TLR9–IFN-I signaling. This cascade subsequently drives monocyte and neutrophil activation, enhances NETosis, and promotes the release of citrullinated histone H3 (CitH3), a NETosis component that exacerbates mitochondrial dysfunction and systemic inflammation, ultimately accelerating the transition to HF. Our team has developed a novel humanized monoclonal antibody against CitH3 (hCitH3-mAb), optimized via AI-guided design and produced under GMP conditions. Preclinical studies demonstrate that hCitH3-mAb confers protection in rodent models of MI and sepsis by neutralizing CitH3, suppressing inflammatory interferon responses, and improving mitochondria function. The specific aims of this project are: Aim 1 - define the role of pDCs and the pDC-neutrophil axis in mediating early myocardial IRI via IFN-I signaling, NETosis, and mitochondrial dysfunction; Aim 2 - characterize activation of the cardio-splenic-neutrophil axis and delineate the cfDNA/CitH3-HMGB1-TLR9–IFN-I and downstream inflammasome signaling pathways; and Aim 3 - evaluate the therapeutic efficacy of hCitH3-mAb and pDC modulation, individually and in combination, in mitigating inflammation and improving cardiac outcomes in rodent and porcine models of MI and post-MI HF. This proposal is highly innovative, integrating systems immunology, cardio-metabolic profiling, and translational therapeutics to target a previously underexplored mechanism - CitH3-mediated immune-metabolic dysfunction. By bridging fundamental discoveries with a first-in-class therapeutic candidate (hCitH3-mAb), this work is uniquely positioned to advance new clinical strategies for limiting reperfusion injury and improving post-MI outcomes. Ultimately, this research will yield new insights into how innate immune activation governs cardiac injury and repair and may lead to transformative therapies that prevent progression to heart failure in MI patients.