Interactions Between Immune and Cardiac Cells During Heart Recovery After Ischemic Heart Injury
Myocardial infarction (MI) is characterized by a marked cellular inflammatory response. CD45pos immune cells rapidly infiltrate injured myocardium, their numbers peaking at day 5 after MI when they become almost as abundant as all CD45neg non-myocyte cells (endothelial cell, fibroblasts, myofibroblasts, smooth muscle cells etc) combined (Fig. 1).
Myeloid cells are the majority of infiltrating cells during acute inflammatory and early reparative phases, and contribute to both pro-inflammatory and anti-inflammatory reactions. Our laboratory is primarily interested in studying the role of myeloid cells in the activation of cardiac progenitor cells and microvascular endothelial cells. We are currently characterizing the role of immune cells in the development of specific phenotype of cardiac mesenchymal stem-like cells using in vitro co-culture of conditionally immortalized cardiac Sca-1posCD31neg cells and different subpopulations of myeloid cells, including Ly6Gpos neutrophils, Ly6Chigh and Ly6Clow/neg monocytes, F4/80pos macrophages and monocyte-derived dendritic cells, generated from bone marrow derived lineage negative hematopoietic progenitor cells (HPC). We also investigating the molecular mechanisms involved in effects of adenosine differentiated dendritic cells (ADDC) on proliferation and morphogenic activity of microvascular endothelial cells.
NRG-1/ERBB Signaling in Myeloid Cells
Neuregulins (NRGs) belong to the epidermal growth factor (EGF) superfamily of transmembrane growth factors and included four members: NRG-1, NRG-2, NRG-3, and NRG-4. Among all neuregulins, NRG-1 has been intensively studied due to its essential role in cardiac development and in regulation of the adult cardiovascular system adaptation to physiological and pathological stress. NRGs signal through neuregulin receptors which include ERBB2, ERBB3 and ERBB4. NRG-1 binds to ERBB3 or ERBB4, and induces homo- and- heterodimer formation with each other (ERBB3/4 heterodimer, ERBB4/4 homodimer) or with ERBB2 (ERBB3/2 or ERBB4/2 heterodimers). ERBB2 has no ligand binding ability; its involvement in NRG-1 signaling is dependent upon heterodimerization with ERBB3 or ERBB4. Dimerization followed by tyrosine phosphorylation results in subsequent activation of downstream intracellular mediators of signaling including PI3K/AKT, Src/FAK, extracellular-regulated kinase (ERK1/2), nitric oxide synthase and cardiac myosin light chain kinase (cMLCK) (Fig. 2).
The protective effect of NRG-1 has been shown in a variety of pathophysiological cardiovascular conditions, including ischemic and anthracycline heart injury, and heart failure. The current paradigm holds non-immune cells as a primary target for protective effects of NRG-1. Our preliminary data, however, indicate that human monocytes express ERBB2 and ERBB3 receptors and NRG-1 signaling pathway in myeloid cells contributes to resolution of inflammation by promoting the functional shift from cytokine-secreting “pro-inflammatory” toward phagocytic “pro-resolution” phenotype (Fig. 3).
To study this phenomenon, we have developed a novel mouse model with cell type-specific deletion of Erbb3 gene expression in myeloid cells (ERBB3MyeKO).
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Adjunct Assistant Professor, Division of Cardiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee
Faculty Scientist I, Maine Medical Center Research Institute, Scarborough, Maine
Member of the Graduate Faculty, Graduate School of Biological Sciences, University of Maine, Orono, ME
Assistant Professor of Medicine, Tufts University School of Medicine, Boston MA
American Society for Pharmacology and Experimental Therapeutics
Member, American Heart Association