Emergency Granulopoiesis in Ventricular Remodeling - Myocardial infarction (MI) activates an acute immune response to instigate a wound-healing response. The coincidence of these two processes suggests a relationship between the two. Activation of an acute response involves the recruitment and activation of massive numbers of neutrophils. Studies in patients show that increases in circulating neutrophils, even within the normal range, predict cardiovascular disease. Likewise, the number of neutrophils in circulation at the time of MI correlates with the severity of ventricular dysfunction. Yet, systemic depletion of neutrophils in mice prior to MI impairs wound healing response and results in ventricle dilatation. Hence, there may be a balance between too many and too few neutrophils. Collectively, these observations demonstrate a balance between the processes of inflammation and scar formation, and the extent to which this balance is perturbed could drive pathology. We contend, however, that neutrophil abundance alone is not the complete picture. Neutrophils are among the shortest-lived immune cells and are continuously produced via granulopoiesis. Despite the inexorable nature of this process, acute increases in neutrophil production in response to stress occur, and such demand-driven (or emergency) granulopoiesis may impact neutrophil phenotype and function. Yet, the extent to which and how emergency granulopoiesis contributes to functional diversity and scar formation is not known. Given this gap in knowledge related to how neutrophil function is regulated after MI, we posit that the functional diversity—not simply total numbers—of neutrophils dictates the extent to which the immune response promotes or antagonizes ventricular remodeling after MI. furthermore, there is lack of clarity on how heart communicates to bone marrow to instigate emergency granulopoiesis. This project will identify neutrophil-specific events involved in tissue inflammation and ventricular remodeling, delinate the role of activated T cells in regulation of emergency granulopoiesis in bone marrow. The main objectives of this proposal are to: i) delineate the role of T cells in activation of emergency granulopoiesis after MI; ii) elucidate the impact of emergency granulopoiesis on neutrophil dynamics and phenotype; iii) determine the role of neutrophil produced via emergency granulopoiesis on monocyte/macrophage dynamics after MI; vi) test the extent to which neutrophil produced via emergency granulopoiesis contribute to ventricular remodeling after MI. This project will create substantial knowledge about the mechanisms regulating emergency granulopoiesis after MI. Moreover, we will establish how neutrophils emergency granulopoiesis neutrophils regulate tissue inflammation and contribute to ventricular remodeling, thereby establishing fundamental, innovative concepts at the nexus between inflammation and ventricular structure and function.
