CCR6 Deficiency Increases Infarct Size after Murine Acute Myocardial Infarction.

David Schumacher,Erik A L Biessen,Erwin Wijnands,Emiel P C Van Der Vorst,Joachim Jankowski,Frank Tacke,Sergio A Lira,Anjana Singh,Adelina Curaj,Elisa A Liehn

doi:10.3390/biomedicines9111532

Abstract

Ischemia-reperfusion injury after the reopening of an occluded coronary artery is a major cause of cardiac damage and inflammation after acute myocardial infarction. The chemokine axis CCL20-CCR6 is a key player in various inflammatory processes, including atherosclerosis; however, its role in ischemia-reperfusion injury has remained elusive. Therefore, to gain more insight into the role of the CCR6 in acute myocardial infarction, we have studied cardiac injury after transient ligation of the left anterior descending coronary artery followed by reperfusion in Ccr6−/− mice and their respective C57Bl/6 wild-type controls. Surprisingly, Ccr6−/− mice demonstrated significantly reduced cardiac function and increased infarct sizes after ischemia/reperfusion. This coincided with a significant increase in cardiac inflammation, characterized by an accumulation of neutrophils and inflammatory macrophage accumulation. Chimeras with a bone marrow deficiency of CCR6 mirrored this adverse Ccr6−/− phenotype, while cardiac injury was unchanged in chimeras with stromal CCR6 deficiency. This study demonstrates that CCR6-dependent (bone marrow) cells exert a protective role in myocardial infarction and subsequent ischemia-reperfusion injury, supporting the notion that augmenting CCR6-dependent immune mechanisms represents an interesting therapeutic target.

Highlights

Acute myocardial infarction (AMI), caused by coronary artery occlusion resulting in dysfunctional myocardium, is one of the leading causes of death worldwide [1]
The ejection fraction and stroke volume were significantly decreased in Ccr6−/− mice (20% and 30%, respectively, compared to wildtype controls), whereas the left ventricular end-systolic volume was strongly, though not significantly, increased (Figure 1C–E)
These data clearly indicate that deficiency of CCR6 worsens cardiac function after ischemia-reperfusion injury

Summary

Introduction

Acute myocardial infarction (AMI), caused by coronary artery occlusion resulting in dysfunctional myocardium, is one of the leading causes of death worldwide [1]. Biomedicines 2021, 9, 1532 standard therapies are reperfusion strategies for restoring blood flow [2], these may result in paradoxical cardiomyocyte dysfunction and worsen tissue damage in a process called ischemia-reperfusion injury [3]. This ischemic cell death eventually results in the formation of post-AMI cardiac fibrosis, leading to the formation of a fibrotic scar [4]. The recruitment of these inflammatory cells is controlled by chemokines that are released by the ischemic heart Several chemokines, such as CCL2 and CXCL12, have been shown to be involved in the AMI response and the resulting cardiac necrosis and fibrosis [7,8]. It could be shown that CCL5 plays a role in AMI [12,13,14], reducing cardiac injury/inflammation by reducing neutrophil and inflammatory monocyte infiltration

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