Blood Milieu in Acute Myocardial Infarction Reprograms Human Macrophages for Trauma Repair

Margaux A C Fontaine; Han Jin; Mick Gagliardi; Mat Rousch; Erwin Wijnands; Monika Stoll; Xiaofei Li; Leon Schurgers; Chris Reutelingsperger; Casper Schalkwijk; Nynke M S van den Akker; Daniel G M Molin; Lars Gullestad; Jan Eritsland; Pavel Hoffman; Mona Skjelland; Geir Ø Andersen; Pål Aukrust; Joël Karel; Evgueni Smirnov; Bente Halvorsen; Lieve Temmerman; Erik A L Biessen

doi:10.1002/advs.202203053

Blood Milieu in Acute Myocardial Infarction Reprograms Human Macrophages for Trauma Repair

Adv Sci (Weinh). 2023 Feb;10(5):e2203053. doi: 10.1002/advs.202203053. Epub 2022 Dec 16.

Authors

Margaux A C Fontaine^{1

2}, Han Jin^{1

2}, Mick Gagliardi^{1

3}, Mat Rousch^{1

2}, Erwin Wijnands^{1

2}, Monika Stoll^{1

4}, Xiaofei Li², Leon Schurgers^{1

5}, Chris Reutelingsperger^{1

5}, Casper Schalkwijk^{1

6}, Nynke M S van den Akker^{1

3}, Daniel G M Molin^{1

3}, Lars Gullestad^{7

8}, Jan Eritsland⁹, Pavel Hoffman⁹, Mona Skjelland^{10

11}, Geir Ø Andersen⁹, Pål Aukrust^{10

12}, Joël Karel¹³, Evgueni Smirnov¹³, Bente Halvorsen¹⁰, Lieve Temmerman^{1

2}, Erik A L Biessen^{1

2

14}

Affiliations

¹ Cardiovascular Research Institute Maastricht University Medical Center (CARIM), Maastricht University, Maastricht, The Netherlands.
² Department of Pathology, Maastricht University, Maastricht, The Netherlands.
³ Department of Physiology, Maastricht University, Maastricht, The Netherlands.
⁴ Institut für Humangenetik, Westfälische Wilhelms-Universität Münster, Münster, Germany.
⁵ Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
⁶ Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands.
⁷ Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁸ K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway.
⁹ Department of Cardiology, Oslo University Hospital Ullevål, University of Oslo, Oslo, Norway.
¹⁰ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
¹¹ Department of Neurology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
¹² Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
¹³ Department of Data Science and Knowledge Engineering (DKE), Maastricht University, Maastricht, the Netherlands.
¹⁴ Institute for Molecular Cardiovascular Research (IMCAR), Universitätsklinikum Aachen, Aachen, Germany.

Abstract

Acute myocardial infarction (AMI) is accompanied by a systemic trauma response that impacts the whole body, including blood. This study addresses whether macrophages, key players in trauma repair, sense and respond to these changes. For this, healthy human monocyte-derived macrophages are 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 are validated in an independent cohort at functional level (n = 47 AMI, n = 25 control) and in a public dataset. AMI serum exposure results in an overt AMI signature, enriched in debris cleaning, mitosis, and immune pathways. Moreover, gene networks associated with AMI and with poor clinical prognosis in AMI are identified. Network-guided drug screening on the latter unveils prostaglandin E2 (PGE2) signaling as target for clinical intervention in detrimental macrophage imprinting during AMI trauma healing. The 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.

Keywords: acute myocardial infarction; heart failure; inflammation; macrophage reprogramming; plasticity; repair.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Gene Regulatory Networks
Humans
Macrophages* / metabolism
Myocardial Infarction* / metabolism
Prognosis

Abstract

Publication types

MeSH terms

Grants and funding