Phagocyte Crosstalk in the Balance of Inflammation & Cardiac Disease

Thorp Project Summary Abstract Acute ischemic injury and heart failure (HF) are significant causes of morbidity and mortality that lack effective therapeutic strategies. Though diverse in their etiology, a common and critical contributor to their disease pathophysiology is the chronically activated macrophage phagocyte. As such, the resolution of cardiac inflammation through selective dampening of macrophge hyperactivity and the promotion of inflammation resolution, has the potential to ameliorate pathophysiology and improve heart health. In the case of HF, which has been earmarked as a research priority by the National Institutes of Health, risk factors such as high fat and hypertension are commonly present and directly contribute to chronic inflammation. During cardiac injuruy and HF, the extent of inflammation and inflammatory macrophages in the myocardium has been linked to the degree of cardiac fibrosis and myocardial stress, and this likely contributes to impaired cardiac performance. However, underlying causal mechanisms and immune molecular protagonists remain incomplete. A similar lack of understanding pertains to how innate inflammation contributes to crosstalk with other cells found in the heart, including cardiac lymphatics. In this setting, cell subsets and molecular factors that regulate inflammation resolution and tissue repair remain unclear. Taken together, our studies will focus on and identify key and maladaptive immunometabolic signaling pathways specific to cardiac disease. In the case of heart failure, we will examine on how risk factors synergize to rewire macrophage signaling circuits that fuel chronic cardiac inflammation. We will also elucidate new pathways by which macrophages communicate with progenitor cells, the underlying molecular mechanisms, and the potential of therapeutic amelioration. Our overall objectives leverage newly generated and cutting-edge experimental tools through approaches in experimental animals and humans. These studies will combine improved basic understanding of novel and disease-specific cellular mechanisms with the identification of new therapeutic candidates for heart failure, inflammation resolution, and tissue inury.