Chemokine-driven inflammation plays an important role in the reparative response following myocardial infarction and is critically involved in the pathogenesis of adverse remodeling. Differential expression of chemokine receptors by monocyte and lymphocyte subsets governs their trafficking in the infarcted myocardium resulting in infiltration with subpopulations that exhibit distinct functional properties. We propose that beyond their involvement in initiation and activation of the post-infarction inflammatory reaction, chemokine-mediated interactions also play an important role in suppression of inflammation through recruitment of leukocyte subsets with inhibitory properties. Our studies suggest that signaling through the CC chemokine receptor 5 (CCR5) mediates recruitment of suppressive monocyte subsets and regulatory T cells (Tregs), a CD4+ T lymphocyte subpopulation with an essential role in regulation of immune responses. Accordingly, the objective of the current proposal is to investigate the role of Tregs and inhibitory monocyte subpopulations in regulation of post-infarction inflammation, to study the molecular signals responsible for their protective effects, and to explore the role of chemokine signaling in their recruitment in the infarcted myocardium. These concepts will be examined in three specific aims:
Specific aim 1 : to investigate the role of monocyte subsets with anti-inflammatory properties in controlling the post-infarction inflammatory response.
Specific aim 2 : to study the involvement of Tregs in inhibition of inflammatory injury, in prevention of excessive matrix degradation and in protection from the development of adverse remodeling following myocardial infarction.
Specific aim 3 : to investigate chemokine/chemokine receptor interactions responsible for recruitment of Tregs and effector T cells in the infarcted myocardium. Chemokine-mediated suppression of inflammation through recruitment of regulatory mononuclear cell subpopulations appears to play an essential role in cardiac repair and protects from the development of adverse remodeling. Understanding the effects of inhibitory monocytes and Tregs may identify novel therapeutic targets for pharmacologic interventions and cell therapy in patients with myocardial infarction.
The proposed project explores the role of monocyte subsets and regulatory T cells in preventing uncontrolled inflammation and excessive injury in myocardial infarction. Chemokine-mediated interactions responsible for recruitment of suppressive mononuclear cell subpopulations may play an essential protective role in the pathogenesis of adverse cardiac remodeling. The findings may identify novel therapeutic targets for pharmacologic interventions and cell therapy in patients with acute myocardial infarction.
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|Saxena, Amit; Russo, Ilaria; Frangogiannis, Nikolaos G (2016) Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges. Transl Res 167:152-66|
|Frangogiannis, Nikolaos G (2016) Fibroblast-Extracellular Matrix Interactions in Tissue Fibrosis. Curr Pathobiol Rep 4:11-18|
|Frunza, Olga; Russo, Ilaria; Shinde, Arti V et al. (2016) Authors' Reply. Am J Pathol 186:2234-5|
|Prabhu, Sumanth D; Frangogiannis, Nikolaos G (2016) The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. Circ Res 119:91-112|
|Chen, Bijun; Frangogiannis, Nikolaos G (2016) Macrophages in the Remodeling Failing Heart. Circ Res 119:776-8|
|Frunza, Olga; Russo, Ilaria; Saxena, Amit et al. (2016) Myocardial Galectin-3 Expression Is Associated with Remodeling of the Pressure-Overloaded Heart and May Delay the Hypertrophic Response without Affecting Survival, Dysfunction, and Cardiac Fibrosis. Am J Pathol 186:1114-27|
|Frangogiannis, Nikolaos G (2016) The Functional Pluralism of Fibroblasts in the Infarcted Myocardium. Circ Res 119:1049-1051|
|Russo, Ilaria; Frangogiannis, Nikolaos G (2016) Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol 90:84-93|
|Frangogiannis, Nikolaos G (2015) Pathophysiology of Myocardial Infarction. Compr Physiol 5:1841-75|
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