Elucidating the Role of IL-1B Signaling in Shaping the Cardiac Immune Landscape After Injury

PROJECT SUMMARY Cardiovascular diseases such as coronary artery disease, heart failure, and arrhythmia contribute significantly to morbidity and mortality worldwide. Cardiac inflammation plays a significant role in disease pathogenesis, and cytokines like the interleukin-1 (IL-1) family contribute significantly to acute and chronic inflammation. Therapeutic approaches that inhibit IL-1β signaling have been shown to improve cardiovascular outcomes in patients with heart failure. However, the precise cellular targets of the IL-1 cytokine family in the heart remain poorly defined, limiting additional therapeutic development. The heart contains two main populations of macrophages: CCR2- resident macrophages and CCR2+ monocyte-derived macrophages, the latter being a significant source of IL-1β during cardiac injury. I have generated preliminary data indicating that IL-1β signaling modulates immune cell behavior and differentiation. The central hypothesis of this research is that IL-1 signaling to infiltrating monocytes and derived macrophages promotes myocardial inflammation by driving their differentiation towards pro-inflammatory cell states, leading to adverse cardiac remodeling. Aim 1 seeks to define the impact of IL-1β signaling to infiltrating CCR2+ monocytes and derived macrophages on cardiac remodeling and fibrosis. Using transgenic Ccr2CreERT2IL1rf/fRosa26tdTomato mice, I will conditionally knock out the IL-1 receptor in CCR2+ monocytes and macrophages and evaluate the effects on myocardial inflammation, fibrosis, and remodeling in two models of cardiac injury: pressure overload (Angiotensin II/Phenylephrine infusion) and ischemia-reperfusion (IRI). This aim will clarify whether IL-1 signaling to CCR2+ macrophages is a viable therapeutic target to mitigate adverse remodeling. Aim 2 investigates the mechanisms through which IL-1β signaling shapes the cardiac immune landscape and immune cell differentiation. By leveraging genetic lineage tracing (Arg1tdT-CreRosa26ZsGreen) and spatial transcriptomics, this aim will explore how IL-1 signaling influences the differentiation trajectories of infiltrating monocytes and their progeny. Computational analyses will be used to examine the regional organization and kinetics of immune cell differentiation during cardiac injury, with the goal of identifying reparative and pathological immune niches within the heart. Overall, this research will address critical gaps in understanding the contributions of IL-1 signaling in cardiac inflammation and remodeling. Defining how IL-1 signaling drives immune cell behavior and contributes to adverse cardiac outcomes will provide key insights into the potential mechanisms underlying IL-1-targeted therapies. Additionally, this work will help inform strategies to enhance the efficacy and safety of these therapies, with the ultimate goal of improving clinical outcomes for heart failure patients.