Leukocyte trafficking during acute myocardial infarction – the role of novel key players and their potential as therapeutic targets –

• Applicant: Professor Dr. Hendrik Sager
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515567441

Background and preliminary data: Myocardial infarction is a major contributor to morbidity and mortality worldwide. It inflicts a sterile wound on the heart which recruits hundreds of thousands of monocytes from the blood. Recruited monocytes differentiate into macrophages which remove necrotic debris, release inflammatory mediators, and consequently play a pivotal role in cardiac injury and repair. The bone marrow responds to cardiac injury with a transient increase in monocyte production, hence meeting the high demand of these cells. Apart from this quantitative response of the bone marrow little is known whether the bone marrow also provides qualitatively altered monocytes during the course of MI. Our preliminary results show that the bone marrow responds to MI and provides an altered monocyte repertoire in terms of numbers and function and hence may remotely control cardiac monocyte/macrophage accumulation and cardiac wound healing. CD209 – a yet poorly described cell adhesion molecule – may be crucially involved in monocyte recruitment to the heart as our preliminary data reveal that: 1. Monocytes with a strong cardiac recruitment profile show high CD209 levels. 2. Vice versa, monocytes with a weak cardiac recruitment profile show low CD209 levels. 3. Monocytes with CD209 overexpression show superior adhesion to endothelial cells. Hypothesis: We hypothesize that the bone marrow remotely controls cardiac inflammation after ischemia by supplying phenotypically/functionally different monocytes during the course of MI. According to our preliminary data, the bone marrow provides monocytes with strong recruitment profiles at the beginning of the inflammatory phase and monocytes with weak recruitment profiles toward the end of the inflammatory phase. We will probe whether this differential recruitment is mediated through altered monocytic expression of CD209 – a yet poorly described cell adhesion molecule. Impact of the proposed study: Monocytes expand rapidly in the heart upon myocardial ischemia and are critically involved in infarct healing and post-MI remodeling. Adverse remodeling is a major contributor to post-MI complications, such as heart failure and malignant arrhythmias. The project described here seeks to investigate qualitative/functional alteration of the monocyte repertoire after MI. Our study will make a significant scientific impact by 1. providing unprecedented, comprehensive mechanistic insights into qualitative and quantitative alterations of the monocyte repertoire in response to MI. 2. challenging the paradigm that monocyte/macrophage function is predominantly inflicted by the local environment after tissue infiltration, and instead proposes that functional priming of monocytes/macrophages already occurs in the bone marrow prior to egress and recruitment to injured tissues. 3. identifying new therapeutic targets for modifying the inflammatory response after MI to ultimately improve infarct healing.

• DFG Programme: Research Grants