Zhang Shuang, Yeap Xin-Yi, Grigoryeva Lubov, Dehn Shirley, DeBerge Matthew, Tye Michael, Rostlund Emily, Schrijvers Dorien, Zhang Zheng Jenny, Sumagin Ronen, Tourtellotte Warren G, Lee Daniel, Lomasney Jon, Morrow John, Thorp Edward B
Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA; Surgery-Organ Transplantation, Northwestern University, Chicago, IL, USA.
University of Antwerp, Belgium.
J Mol Cell Cardiol. 2015 Oct;87:171-9. doi: 10.1016/j.yjmcc.2015.08.009. Epub 2015 Aug 24.
Mobilization of the innate immune response to clear and metabolize necrotic and apoptotic cardiomyocytes is a prerequisite to heart repair after cardiac injury. Suboptimal kinetics of dying myocyte clearance leads to secondary necrosis, and in the case of the heart, increased potential for collateral loss of neighboring non-regenerative myocytes. Despite the importance of myocyte phagocytic clearance during heart repair, surprisingly little is known about its underlying cell and molecular biology.
To determine if phagocytic receptor MERTK is expressed in human hearts and to elucidate key sequential steps and phagocytosis efficiency of dying adult cardiomyocytes, by macrophages.
In infarcted human hearts, expression profiles of the phagocytic receptor MER-tyrosine kinase (MERTK) mimicked that found in experimental ischemic mouse hearts. Electron micrographs of myocardium identified MERTK signal along macrophage phagocytic cups and Mertk-/- macrophages contained reduced digested myocyte debris after myocardial infarction. Ex vivo co-culture of primary macrophages and adult cardiomyocyte apoptotic bodies revealed reduced engulfment relative to resident cardiac fibroblasts. Inefficient clearance was not due to the larger size of myocyte apoptotic bodies, nor were other key steps preceding the formation of phagocytic synapses significantly affected; this included macrophage chemotaxis and direct binding of phagocytes to myocytes. Instead, suppressed phagocytosis was directly associated with myocyte-induced inactivation of MERTK, which was partially rescued by genetic deletion of a MERTK proteolytic susceptibility site.
Utilizing an ex vivo co-cultivation approach to model key cellular and molecular events found in vivo during infarction, cardiomyocyte phagocytosis was found to be inefficient, in part due to myocyte-induced shedding of macrophage MERTK. These findings warrant future studies to identify other cofactors of macrophage-cardiomyocyte cross-talk that contribute to cardiac pathophysiology.
调动先天性免疫反应以清除和代谢坏死及凋亡的心肌细胞是心脏损伤后心脏修复的先决条件。死亡心肌细胞清除的动力学欠佳会导致继发性坏死，就心脏而言，还会增加相邻非再生性心肌细胞附带损失的可能性。尽管在心脏修复过程中，心肌细胞吞噬清除至关重要，但令人惊讶的是，对其潜在的细胞和分子生物学却知之甚少。
确定吞噬受体MERTK是否在人类心脏中表达，并阐明巨噬细胞对成年死亡心肌细胞进行吞噬的关键连续步骤和吞噬效率。
在梗死的人类心脏中，吞噬受体MER-酪氨酸激酶（MERTK）的表达谱与实验性缺血小鼠心脏中的相似。心肌的电子显微镜照片显示，巨噬细胞吞噬杯周围有MERTK信号，且Mertk-/-巨噬细胞在心肌梗死后所含的消化心肌细胞碎片减少。原代巨噬细胞与成年心肌细胞凋亡小体的体外共培养显示，相对于驻留心脏成纤维细胞，吞噬作用减弱。清除效率低下并非由于心肌细胞凋亡小体尺寸较大，吞噬突触形成之前的其他关键步骤也未受到显著影响；这包括巨噬细胞趋化作用以及吞噬细胞与心肌细胞的直接结合。相反，吞噬作用受到抑制与心肌细胞诱导的MERTK失活直接相关，通过基因删除MERTK蛋白水解敏感位点可部分挽救这种失活。
利用体外共培养方法模拟梗死期间体内发现的关键细胞和分子事件，发现心肌细胞吞噬作用效率低下，部分原因是心肌细胞诱导巨噬细胞MERTK脱落。这些发现值得未来开展研究，以确定促成心脏病理生理学的巨噬细胞-心肌细胞相互作用的其他辅助因子。
