The MIF protein family in cardiac ischemia and heart failure: molecular mechanisms and translational avenues

巨噬细胞移动抑制因子（Macrophage migration inhibitory factor，MIF）是一种结构独特的炎症细胞因子，具有趋化因子样活性，在人体先天免疫和炎症反应中起关键的上游介导作用。它是MIF蛋白家族的创始成员，该家族包括D-多巴色素互变异构酶（D-DT）/MIF-2以及一组细菌互变异构酶和跨界的MIF直系同源物。通过其独特的表达特征，如免疫细胞、内皮细胞和心肌细胞中的半组成性表达和炎症刺激后的快速释放，MIF被理想地定位为充当早期炎症和细胞应激传感器。由于这种性质和其炎症能力，发现MIF是急性和慢性炎症和自身免疫性疾病（如脓毒性休克和动脉粥样硬化）的关键介质。尽管MIF在心血管疾病中的活性最初是在动脉粥样硬化的背景下定义的，但我们和其他人在过去4-6年的工作现在已经确定MIF在心血管疾病中的作用是复杂的，并且涉及对缺血应激的反应中的基本作用。在心脏中，MIF由缺血性心肌细胞、成纤维细胞或内皮细胞释放，并通过自分泌/旁分泌信号传导起作用。我们小组和其他人的研究已经确定了MIF作为局部心脏细胞因子的独特作用，具有时相特异性心脏保护和加重活性。我们在第一个资助期发表的工作表明，虽然心肌缺血/再灌注期间增加的MIF水平与器官功能障碍发展的风险降低相关，但高MIF-2/D-DT水平可预测心房颤动和肺炎的发展，表明MIF同系物在心肌缺血/再灌注损伤中的独特功能。我们自己的翻译发现，以及从最近的荟萃分析中获得的数据，以及实际专家团队的总体共识，使我们将重点从RIPC问题更多地转向对围手术期MIF增加的器官保护作用的深入机制理解，以及心肌缺血/再灌注后心脏的以下适应过程，这经常导致与重大医疗保健相关费用相关的发病率的发展。

Macrophage migration-inhibitory factor (MIF) is a structurally unique, inflammatory cytokine with chemokine-like activities that acts as a key upstream mediator in innate immunity and inflammation in the human body. It is the founding member of the MIF protein family, which encompasses D-dopachrome tautomerase (D-DT)/MIF-2 as well as a group of bacterial tautomerases and MIF orthologs across kingdoms. Through its unique expression characteristics such as semi- constitutive expression and rapid release upon inflammatory stimulation in immune cells, endothelial cells and cardiomyocytes, MIF is ideally positioned to serve as an early inflammatory and cell- stress sensor. Owing to this property and its inflammatory capacity, MIF was found to be a pivotal mediator in acute and chronic inflammatory and autoimmune diseases, such as septic shock and atherosclerosis. Although MIF activities in cardiovascular disease were initially defined in the context of atherosclerosis, work by us and others in the past 4-6 years has now established that MIF’s role in cardiovascular disease is complex and involves a fundamental role in the response to ischemic stress. In the heart, MIF is released by ischemic cardiomyocytes, fibroblasts, or endothelial cells and acts by auto-/paracrine signaling. Studies from our group and others have identified a unique role for MIF as a local cardiac cytokine with phase- specific cardioprotective and exacerbating activities. Our published work in the first funding period demonstrated that while increased MIF levels during myocardial ischemia/reperfusion were associated with a reduced risk for the development of organ dysfunctions, high MIF-2/D- DT levels were predictive of the development of atrial fibrillation and pneumonia, suggesting distinct functions of the MIF homologs in myocardial ischemia/reperfusion injury. Our own translational findings, and data obtained from recent meta-analysis, as well as the overall consensus of actual expert teams, led us to shift our focus from RIPC questions more towards an in-depth mechanistic understanding of the organ-protective effect of the perioperative increase in MIF and towards the following adaptation processes in the heart after myocardial ischemia/reperfusion, which frequently lead to the development of morbidities that are associated with significant healthcare-related costs.