MIF inhibition preserves cardiac function after myocardial ischemia and reperfusion by controlling the monocyte-differentiation and macrophage-polarization

• Applicant: Professor Dr. Peter Lüdike
• Subject Area: Cardiology, Angiology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390971602

Ischemic heart failure (HF) as a consequence of ischemic heart disease is the leading cause of death in the western world. After myocardial ischemia and reperfusion (I/R), activation of innate immune responses is an essential component to limit the extent of cardiac injury and facilitate healing. Recruitment of neutrophils and monocytes to the myocardium denotes the first step of healing, followed by monocyte differentiation into macrophages. Healing requires further a fine-tuned polarization of macrophages into reparative and inflammatory species. The mechanisms controlling monocyte differentiation and macrophage polarization in myocardial I/R are poorly understood yet. Damage-associated molecular patterns (DAMPs) are released from the ischemic myocardium during I/R and have recently emerged as key players in orchestrating this inflammatory response after acute myocardial infarction (AMI). DAMPs are recognized by pattern recognition receptors such as Toll-like receptor 4 (TLR4), which trigger inflammatory signaling cascades. Macrophage migration inhibitory factor (MIF) is a chemokine-like function (CLF) chemokine, an emerging class of molecules that functionally overlaps with the mediator classes of alarmins and DAMPs. MIF controls TLR4 expression in leukemia macrophages and is also released during myocardial I/R and exhibits auto- and intracrine cardioprotective activities. Own studies recently demonstrated that cardioprotection by MIF is prominent in the early phase of reperfusion and the applicant identified S-nitrosation as a novel posttranslational modification of MIF (SNO-MIF), which potentiates the cardioprotective properties of MIF while also regulating its secretion from cardiac tissue during reperfusion. Whether SNO-MIF has altered chemotactic properties and whether it affects monocyte differentiation and macrophage polarization in the heart during I/R stress is unknown. Here, the applicant aims to investigate whether MIF is a regulator of the DAMPs-associated immune response during myocardial I/R and whether modulation of this cascade by S-nitrosation of MIF has the potential to prevent HF after AMI

• DFG Programme: Research Grants