Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia

Author:

Weinberger Tobias1234ORCID,Denise Messerer12,Joppich Markus5ORCID,Fischer Maximilian123ORCID,Garcia Rodriguez Clarisabel4,Kumaraswami Konda12,Wimmler Vanessa12,Ablinger Sonja12,Räuber Saskia126ORCID,Fang Jiahui12,Liu Lulu12,Liu Wing Han1,Winterhalter Julia12,Lichti Johannes1,Thomas Lukas123,Esfandyari Dena37ORCID,Percin Guelce8,Matin Sandra9,Hidalgo Andrés910,Waskow Claudia811,Engelhardt Stefan37ORCID,Todica Andrei12,Zimmer Ralf5,Pridans Clare1314ORCID,Gomez Perdiguero Elisa4,Schulz Christian12315ORCID

Affiliation:

1. Medical Clinic I., Department of Cardiology, University Hospital, Ludwig Maximilian University

2. Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine University

3. DZHK (German Centre for Cardiovascular Research), Partner site Munich Heart Alliance

4. Institut Pasteur, Unité Macrophages et Développement de l'Immunité, Département de Biologie du Développement et Cellules Souches

5. LFE Bioinformatik, Department of Informatics, Ludwig Maximilian University

6. Department of Neurology, Medical Faculty, Heinrich Heine University of Düsseldorf

7. Institute of Pharmacology and Toxicology, Technical University Munich

8. Immunology of Aging, Leibniz-Institute on Aging - Fritz-Lipmann-Institute (FLI)

9. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III

10. Vascular Biology and Therapeutics Program and Department of Immunobiology, Yale University School of Medicine

11. Faculty of Biological Sciences, Friedrich-Schiller-University

12. Department of Nuclear Medicine, Ludwig Maximilian University

13. Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh

14. University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute

15. Department of Immunopharmacology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University

Abstract

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

Funder

Deutsches Zentrum für Herz-Kreislaufforschung

Deutsche Forschungsgemeinschaft

LMUexcellent

European Society of Cardiology

Friedrich-Baur Stiftung

Deutsche Stiftung für Herzforschung

Chinese Scholarship Council

Publisher

eLife Sciences Publications, Ltd

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