Differential Contribution of Monocytes to Heart Macrophages in Steady-State and After Myocardial Infarction
Open accessAbstract
Rationale : Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation. Objective : Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b DTR/+ mice and in myocardial infarction. Methods and Results : Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in ≈1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3±3.4%, whereas heart macrophages showed a much lower chimerism of 2.7±0.5% ( P <0.01). Macrophages self-renewed locally through proliferation: 2.1±0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7±1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue-resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin–induced macrophage depletion in CD11b DTR/+ mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation. Conclusions : In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure.
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Because Cx3cr1 is not expressed in fibroblasts and Brd4 is not deleted in that population, the fibroblast gene expression changes reflect a non-cell autonomous effect.
“As Cx3cr1 is not expressed in fibroblasts26 (Extended Data Fig. 1A), and therefore Brd4 is not deleted in this cell population (Extended Data Figs. 2B and 3B-D), the fibroblast gene expression changes reflect a non-cell autonomous effect.”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [26]
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- Authors
- Heidt, T., Courties, G., Dutta, P., Sager, H. B., Sebas, M., Iwamoto, Y., Sun, Y., Da Silva, N., Panizzi, P., van der Laan, A. M., Swirski, F. K., Weissleder, R., & Nahrendorf, M.
- Affiliations
- Harvard University (US)
- From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
- ORCID
- Venue
- Circulation Research
- Published
- 2014-07-07
- Volume
- 115
- Issue
- 2
- Pages
- 284-295
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4082439
- OpenAlex
- W2107915827
- Cited by
- 607
- References
- 21
- Citations by year
- 2026: 39 · 2025: 45 · 2024: 77 · 2023: 73 · 2022: 58 · 2021: 61 · 2020: 59 · 2019: 48 · 2018: 48 · 2017: 36 · 2016: 23 · 2015: 31 · 2014: 9
- FWCI
- 22.46
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-12-05)
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- University of California, San Diego
- National Heart, Lung, and Blood Institute (R01HL117829, HHSN268201000044C, R01HL114477, R01HL095629, R01HL096576, K99HL121076)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069623)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- cardiac macrophages, monocytes, myocardial infarction, tissue-resident macrophages, macrophage self-renewal, macrophage turnover, macrophage depletion, parabiosis, immune surveillance, bacterial phagocytosis, heart failure
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Cell Division, Diphtheria Toxin, Female, Humans, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Monocytes, Myocardial Infarction, Myocardium, Parabiosis, Phagocytosis, Radiation Chimera, Bone Marrow Transplantation, Myocardial Ischemia, Apoptosis, Genes, Reporter, Adoptive Transfer, Receptors, Chemokine, Mice
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