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Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration
Ist Teil von
Circulation (New York, N.Y.), 2019-01, Vol.139 (5), p.663-678
Ort / Verlag
United States: by the American College of Cardiology Foundation and the American Heart Association, Inc
Erscheinungsjahr
2019
Quelle
MEDLINE
Beschreibungen/Notizen
BACKGROUND:Macrophage-associated immune response plays an important role in myocardial ischemia/reperfusion (IR) injury. Dectin-1, expressed mainly on activated myeloid cells, is crucial for the regulation of immune homeostasis as a pattern recognition receptor. However, its effects and roles during the myocardial IR injury remain unknown.
METHODS:Genetic ablation, antibody blockade, or Dectin-1 activation, along with the adoptive bone marrow transfer chimeric model, was used to determine the functional significance of Dectin-1 in myocardial IR injury. Immune cell filtration and inflammation were examined by flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Moreover, Dectin-1 cells were analyzed by flow cytometry in the blood of patients with ST-segment–elevation myocardial infarction and stable patients with normal coronary artery (control).
RESULTS:We demonstrated that Dectin-1 expression observed on the bone marrow–derived macrophages is increased in the heart during the early phase after IR injury. Dectin-1 deficiency and antibody-mediated Dectin-1 inhibition led to a considerable improvement in cardiac function, accompanied by a reduction in cardiomyocyte apoptosis, which was associated with a decrease in M1 macrophage polarization and Ly-6C monocyte and neutrophil infiltration. Activation of Dectin-1 with its agonist had the opposite effects. Furthermore, Dectin-1 contributed to neutrophil recruitment through the regulation of Cxcl1 and granulocyte colony-stimulating factor expression. In addition, Dectin-1–dependent interleukin-23/interleukin-1β production was shown to be essential for interleukin-17A expression by γδT cells, leading to neutrophil recruitment and myocardial IR injury. Furthermore, we demonstrated that circulating Dectin-1CD14CD16 and Dectin-1CD14CD16 monocyte levels were significantly higher in patients with ST-segment–elevation myocardial infarction than in controls and positively correlated with the severity of cardiac dysfunction.
CONCLUSIONS:Our results reveal a crucial role of Dectin-1 in the process of mouse myocardial IR injury and provide a new, clinically significant therapeutic target.