CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T Cells

作者：Guoshuai Feng, Geetika Bajpai, Pan Ma, Andrew L. Koenig, Andrea L. Bredemeyer, Inessa Lokshina, Lulu Lai, Irmgard Förster, Florian Leuschner, Daniel Kreisel, Kory J. Lavine · 发表于：Circulation · 年份：2022 · DOI：10.1161/circulationaha.121.055888 · 被引用次数：137 · 研究领域：Cardiac Fibrosis and Remodeling、Atherosclerosis and Cardiovascular Diseases、Chemokine receptors and signaling

Background: Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2 + monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation. Methods: We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used Ccl17 knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects. Results: We demonstrated that CCL17 is expressed in CCR2 + macrophages and cluster of differentiation 11b + conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17 + macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) sign...