Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis
Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis
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DOI：
10.1084/jem.20181102
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发表时间：
2019-01
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影响因子：
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通讯作者：
L. Weckbach;U. Grabmaier;A. Uhl;S. Gess;Felicitas Boehm;A. Zehrer;R. Pick;M. Salvermoser;
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文献类型：
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作者：
L. Weckbach;U. Grabmaier;A. Uhl;S. Gess;Felicitas Boehm;A. Zehrer;R. Pick;M. Salvermoser;
扩张型心肌病引起的心力衰竭常由心肌炎引起。然而，心肌炎的发病机制仍不完全清楚。在这里，我们报告的存在下，中性粒细胞胞外陷阱（NET）在心肌炎患者和小鼠的心脏组织。在小鼠实验性自身免疫性心肌炎（EAM）中抑制NET形成可显著减少疾病急性期的炎症。靶向介导体外NET形成的细胞因子中期因子（MK），不仅可以减弱体内NET形成和多形核中性粒细胞（PMN）的浸润，还可以减少纤维化并保留EAM期间的收缩功能。低密度脂蛋白受体相关蛋白1（LRP 1）作为MK诱导的PMN募集以及NET形成的功能相关受体。总之，NETosis在很大程度上有助于心肌炎的发病机制，并可能通过MK驱动心脏炎症，MK促进PMN运输和NETosis。因此，MK以及NET可能代表用于治疗心脏炎症的新的治疗靶点。
Heart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Low-density lipoprotein receptor–related protein 1 (LRP1) acts as the functionally relevant receptor for MK-induced PMN recruitment as well as NET formation. In summary, NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation.