The role of IL-3 in myocardial infarction

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Myocardial infarction (MI) is a leading cause of death worldwide and occurs most often when thrombotic or embolic occlusion of coronary arteries interrupts blood supply. We recognize that the consequence of a coronary occlusion is not all or nothing, but can vary in ways that correlate with clinical outcomes. Expansive remodeling of the left ventricle, for example, predicts poor long-term outcomes because the ventricles often pump ineffectively, which leads to functional mitral regurgitation and to the syndrome of heart failure, a major impediment to quality of life and drain on healthcare resources. As a result, there has been increased focus on the healing response that occurs after the initial ischemic insult. It has been shown that a large number of inflammatory Ly-6Chigh monocytes, which originate the bone marrow and spleen, accumulate in the myocardium over the first 2 days. Five days later, the inflammatory Ly-6Chigh monocyte phase gives way to Ly-6Clow reparative macrophages, thereby inducing myocardial healing. Interestingly, Swirski et al. could show that Interleukin 3 (IL-3) is a potent inducer of inflammatory monocyte production leading to increased accumulation of Ly-6Chigh monocytes in the infarcted myocardium. This observation seems surprising, since IL-3 is perhaps best known as an inducer of basophils and mast cells and contributor to contact hypersensitivity. In this approach, we will study the role of IL-3 in post MI inflammation and repair. We will therefore utilize IL-3-deficient mice and mice treated with an IL-3 antibody. MI will be induced by LAD (left anterior descending artery) ligation. Furthermore we are aiming to identify the cell type/tissue responsible for IL-3 secretion in the context of MI. To answer these questions detailed histologic analysis of the heart in experimental groups, detailed cellular and molecular profiling in the bone marrow, blood, and spleen, detailed analysis of leukocyte function by non-invasive functional imaging and analysis of heart function will be performed. These experiments might identify IL-3 as a novel therapeutic approach for the treatment of patients with myocardial infarction.