ADAM10型
外域
炎症
坏死性下垂
CXCL16型
医学
趋化因子
心肌梗塞
细胞生物学
渗透(HVAC)
先天免疫系统
癌症研究
去整合素
免疫学
免疫系统
内科学
生物
金属蛋白酶
细胞凋亡
基质金属蛋白酶
CXCL10型
受体
程序性细胞死亡
生物化学
物理
热力学
作者
Erik Klapproth,Anke Witt,Pauline Klose,Johanna Wiedemann,Nikitha Vavilthota,Stephan R. Künzel,Susanne Kämmerer,Mario Günscht,David Sprott,Mathias Lesche,Fabian Rost,Andreas Dahl,Erik Rauch,Lars Kattner,Silvio Weber,Peter Mirtschink,Irakli Kopaliani,Kaomei Guan,Kristina Lorenz,Paul Säftig,Michael Wagner,Ali El‐Armouche
标识
DOI:10.1038/s41467-022-35331-0
摘要
Abstract After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy. Intriguingly, upon MI in mice, pharmacological ADAM10 inhibition as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, abolished ADAM10-mediated CX3CL1 ectodomain shedding leads to diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.
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