Myocarditis is a heterogeneous inflammatory disease of the heart muscle that constitutes a wide spectrum of inflammatory pathologies. It can manifest from mild subclinical disease to severe outcomes, including cardiogenic shock, life-threatening arrhythmias, and even sudden death. While many patients recover from acute illness associated with myocarditis, the long-term sequelae of myocardial inflammation involves the development of inflammatory dilated cardiomyopathy and chronic heart failure, both for which treatment options are gravely limited. Given that myocarditis is such a highly polymorphic disease and specific clinical guidelines for its treatment do not exist, it is important to identify common underlying mechanisms that drive myocardial inflammation, in order to better prevent morbidity and mortality associated with myocarditis. To-date, most information regarding the pathogenesis of myocarditis has been gleaned from animal models that mimic aspects of autoimmune and viral myocarditis. In these models, CD4+ T cells play a major role in driving inflammation. However, it is still mechanistically unclear how various cytokines produced by these cells can promote myocardial inflammation and disease progression to more serious and fatal outcomes. Interestingly, our preliminary work suggests that interleukin (IL)-3, a cytokine from the colony-stimulating factor (CSF) family, drives inflammation in the heart during the peak of experimental autoimmune myocarditis (EAM). For example, we recently discovered that IL-3-deficient mice are protected from cardiac inflammation in EAM. Upon profiling heart leukocytes, we found that IL-3 is specifically produced by CD4+ T helper (TH) cells at the peak of EAM, and determined that cardiac MHC-II+ macrophages, monocytes, and monocyte-derived dendritic cells (moDC) express the IL-3 receptor (IL-3R) at the peak of EAM, thus identifying these IL-3R+ cells as putative IL-3 responders. Together, these data led us to propose the central hypothesis that IL-3 is essential for driving T cell-mediated cardiac inflammation in myocarditis. Here, I aim to examine IL-3-mediated mechanisms that drive inflammation using two well-characterized mouse models of myocarditis (i.e. EAM and coxsackievirus B3 (CVB3)-induced myocarditis).
My specific aims are as follows: (I) I will assess how IL-3:IL-3R signaling modulates leukocyte dynamics in myocarditis in the heart and periphery. (II) I will define the lineage origin and characteristics of IL-3-producing T cells during myocarditis. (III) Finally, I will also evaluate the efficacy of targeting IL-3/IL-3R signaling myocarditis inflammation and disease outcome. Utilizing genetic knockout mice, various in vivo and in vitro analyses, flow cytometry and cell sorting, molecular biology, histology, and imaging techniques, I aim to determine how IL-3:IL-3R signaling shapes leukocyte function, identify subsets T cells that are drivers of IL-3-mediated cardiac inflammation, and uncover biological targets that are therapeutically relevant for ameliorating myocardial inflammation, hindering disease progression, and preventing sudden death.
The proposed project will provide novel insights into the biology surrounding immune cell crosstalk in the context of cardiac inflammation and/or myocarditis mediated by interleukin (IL)-3. T cell-derived IL-3 has not yet been studied in heart inflammation and infection up to this point, nor has cardiac IL-3 receptor (IL-3R)+ cell function during inflammation. Uncovering the mechanistic role of IL-3 as a pathogenic cytokine in both autoimmune and viral myocarditis may bring IL-3 and IL-3R+ cells to the forefront as therapeutic targets to prevent chronic cardiac inflammation, progression to inflammatory dilated cardiomyopathy, and the development of chronic heart failure or sudden death, which are severe outcomes linked to myocardial inflammation.
