Blood milieu in acute myocardial infarction reprograms human macrophages for trauma repair

Acute myocardial infarction (AMI) is accompanied by a systemic trauma response that impacts on the whole body, including blood. In this study, we addressed whether macrophages, key players in trauma repair, sense and respond to these changes. For this, healthy human monocyte-derived macrophages were exposed to 20% human AMI (n=50) or control (n=20) serum and analyzed by transcriptional and multiparameter functional screening followed by network-guided data interpretation and drug repurposing. Results were validated in an independent cohort at functional level (n=47 AMI, n=25 control) and in a public dataset. AMI serum exposure resulted in an overt AMI signature, enriched in debris cleaning, mitosis, and immune pathways. Moreover, we identified gene networks associated with AMI and with poor clinical prognosis in AMI. Network-guided drug screening on the latter unveiled Prostaglandin E2 (PGE2) signaling as target for clinical intervention in detrimental macrophage imprinting during AMI trauma healing. Our results demonstrate pronounced context-induced macrophage reprogramming by the AMI systemic environment, to a degree decisive for patient prognosis. This offers new opportunities for targeted intervention and optimized cardiovascular disease risk management. Primary human CD14+-derived macrophages growing in 96-wells were exposed to different stimuli for 24h (n=4-6 per condition). Cells were washed, lysed, pooled per condition, and RNAsequencing was performed.