Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration

Abstract

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-1 + CD14 ++ CD16 − and Dectin-1 + CD14 ++ CD16 + 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.

Myocardial ischemia‐reperfusion induced cardiac extracellular vesicles harbour proinflammatory features and aggravate heart injury

“…EVs exert their regulative functions on various immune cells including T cells (Okoye et al., 2014), B cells (Carreras‐Planella et al., 2019), monocyte/macrophages (L et al., 2019) and dendritic cells (Shahir et al., 2020). As a major population of immune cells in heart tissue, macrophages play an important role in the development of heart injury through M1/M2 polarization (Cao et al., 2018; Fan et al., 2018). Different origins of EVs have divergent roles on macrophage polarization.…”

“…Modulation of pro‐inflammatory monocytes or M1 macrophages after MI has cardioprotective effect (Courties et al., 2014; Harel‐Adar et al., 2011). In contrast, promoting the polarization of M2 macrophages can alleviate inflammation and prevent poor ventricular remodelling after MI (Fan et al., 2018; Weirather et al., 2014). Therefore, polarization status of macrophages during MI and IR injury is regarded as a potential therapeutic target.…”

Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling

“…Recent data suggest the involvement of macrophage polarization in cardiovascular diseases, such as chemotherapy-related cardiac injury 11 . Under some condition, monocytes travel to the site of injury and undergo differentiation into either proinflammatory M1 macrophages or antiinflammatory M2 macrophages 12 . In the chemotherapy-related cardiotoxicity, modulating macrophage polarization could partially alleviate cardiac injury 13 .…”

Dendritic Cells as Sensors, Mediators, and Regulators of Ischemic Injury

“…Further evidence shows that HO-1 regulates macrophage activation through the Sirtuin/p53 signaling pathway to drive hepatic death during liver IRI (37). Deletion or inhibition of Dectin-1 can suppress M1 macrophage polarization and alleviate myocardial IRI (38). T cells can continue to localize in injured kidneys for 2 weeks and display an effector-memory and activation phenotype characterized by CD44 hi CD62L − and CD69 + expression, respectively (39).…”