Myocardial infarction and ischemic cardiomyopathy are among the leading causes of mortality in the industrial and developing world. Despite therapies to restore coronary perfusion and limit left ventricular remodeling, many patients develop progressive heart failure and suffer unacceptably high mortality rates. Mechanistically, activation of the innate immune system appears to be a common pathway by which the heart responds to injury. However, considerable debate exists whether innate immune responses represent an adaptive or maladaptive event. Recently, we have uncovered a previously unrecognized complexity within the innate immune system. Using a combination of genetic lineage tracing, flow cytometry, and immunostaining, we have demonstrated that the mouse and human heart contain a complex and heterogeneous array of resident macrophage subsets derived from embryonic and adult monocyte progenitors with differing recruitment dynamics and functions. Under steady state conditions, the heart contains at least 2 functionally distinct resident macrophage subsets: CCR2- and CCR2+ macrophages. Resident CCR2- macrophages are derived from embryonic progenitors (yolk sac and fetal liver) and are maintained locally independent of blood monocyte input. In contrast, resident CCR2+ macrophages are derived from adult bone marrow progenitors and are continually replenished by blood monocytes. More recently, we have demonstrated that in the context of cardiac injury, monocytes enter the heart, replace resident immune cells, and differentiate into multiple macrophage subsets. In this proposal we will test the hypothesis that following cardiac injury monocytes infiltrate the heart and differentiate into distinct macrophages subsets with divergent functions. We further hypothesize that monocyte recruitment and monocyte fate specification are differentially regulated by opposing functions of resident cardiac macrophages: resident CCR2+ macrophages promote monocyte recruitment and the differentiation of inflammatory monocyte-derived macrophages, while resident CCR2- macrophages suppress monocyte recruit and promote the differentiation of reparative monocyte-derived macrophages. Lastly, we will define the molecular mechanism by which resident CCR2+ macrophages recognize injured cardiomyocytes and trigger inflammatory responses. Clinically, the development of therapeutics that uniquely target specific macrophage subsets and/or modulate monocyte fate decisions may offer a new avenue to improve outcomes for patients with ischemic heart disease.

Public Health Relevance

PROJECT NARRITIVE Despite modern technologies, ischemic heart disease continues to represent a major cause or morbidity and mortality worldwide. For patients who suffer a heart attack, the initial extent of cardiac injury and subsequent activation of the innate immune system are major predictors of future outcomes. Paradoxically, innate immune activation in response to cardiac injury has been demonstrated to not only trigger damaging inflammation, but also, is essential for tissue repair. The overarching goal of this proposal is to understand the mechanistic basis by which activation of the innate immune system results in such divergent effects and decipher whether manipulation of the resident and recruited macrophage subsets is sufficient to alter outcomes following ischemic myocardial injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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