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

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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.