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The human heart contains distinct macrophage subsets with divergent origins and functions

Nature Medicine volume 24, pages 1234–1245 (2018)Cite this article

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Abstract

Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a critical determinant of immune responses. In contrast, surprisingly little is known regarding macrophage heterogeneity in humans. Macrophages within the mouse heart are partitioned into CCR2− and CCR2+ subsets with divergent origins, repopulation mechanisms, and functions. Here, we demonstrate that the human myocardium also contains distinct subsets of CCR2− and CCR2+ macrophages. Analysis of sex-mismatched heart transplant recipients revealed that CCR2− macrophages are a tissue-resident population exclusively replenished through local proliferation, whereas CCR2+ macrophages are maintained through monocyte recruitment and proliferation. Moreover, CCR2− and CCR2+ macrophages have distinct functional properties, analogous to reparative CCR2− and inflammatory CCR2+ macrophages in the mouse heart. Clinically, CCR2+ macrophage abundance is associated with left ventricular remodeling and systolic function in heart failure patients. Collectively, these observations provide initial evidence for the functional importance of macrophage heterogeneity in the human heart.

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Fig. 1: The human heart contains distinct populations of CCR2− and CCR2+ macrophages.
Fig. 2: CCR2− and CCR2+ cardiac macrophage populations are maintained through distinct mechanisms.
Fig. 3: Microarray gene expression profiling of CCR2+ monocytes, CCR2− macrophages, and CCR2+ macrophages in the failing human heart.
Fig. 4: CCR2− and CCR2+ macrophages display distinct gene expression profiles.
Fig. 5: CCR2+ cardiac macrophages represent an inflammatory population.
Fig. 6: Macrophage subpopulations are associated with outcome following mechanical unloading.

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Acknowledgements

We acknowledge the Translational Cardiovascular Biorepository at Washington University for providing cardiac tissue specimens. This project was made possible by funding provided from the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CH-II-2015-462, CH-II-2017-628), the Foundation for Barnes-Jewish Hospital (8038-88), and the NHLBI (R01 HL138466, R01 HL139714). K.J.L. is supported by National Institutes of Health (NIH) K08 HL123519 and Burroughs Welcome Fund (1014782). Histology was performed in the DDRCC advanced imaging and tissue analysis core supported by Grant #P30 DK52574. The Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant #UL1TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. S.G.D. is supported by NHLBI R01 HL135121-01, AHA HF 16SFRN29020000-Project 1, and the Nora Eccles Treadwell Foundation. M.N. is supported by NIH HL139598 and the MGH Research Scholar Program. Y.L. is supported by NIH R01HL131908 and R01HL125655. D.K. is supported by NIH P01AI116501 and R01 HL094601, Veterans Administration Merit Review grant 1I01BX002730 and the Foundation for Barnes-Jewish Hospital. M.H. was supported by an MGH ECOR Tosteson and Fund for Medical Discovery Fellowship (2017A052660).

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Authors and Affiliations

  1. Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA

    Geetika Bajpai, Caralin Schneider, Nicole Wong, Andrea Bredemeyer & Kory J. Lavine

  2. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Maarten Hulsmans & Matthias Nahrendorf

  3. Peter Munk Cardiac Center, Ted Rogers Center for Heart Failure Research, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

    Slava Epelman

  4. Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA

    Daniel Kreisel & Akinobu Itoh

  5. Department of Radiology, Washington University School of Medicine, Saint Louis, MO, USA

    Yongjian Liu

  6. Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT, USA

    Thirupura S. Shankar

  7. Division of Cardiothoracic Surgery & Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT, USA

    Craig H. Selzman

  8. Division of Cardiovascular Medicine & Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT, USA

    Stavros G. Drakos

  9. Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, USA

    Kory J. Lavine

  10. Department of Immunology and Pathology, Washington University School of Medicine, Saint Louis, MO, USA

    Kory J. Lavine

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  1. Geetika Bajpai
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Contributions

G.B. performed the flow cytometry, gene expression profiling, and macrophage in vitro assays. C.S. performed and analyzed the immunostaining experiments. A.I. provided cardiac specimens. N.W. assisted with quantitative data analyses. S.G.D., C.H.S., and T.S.S. provided cardiac specimens and clinical data for the LVAD patient cohort. G.B., D.K., M.H., M.N., S.E., Y.L., and A.B. assisted with study design, data interpretation, and manuscript production. K.J.L. was responsible for all aspects of this study including study design, experimental execution, data analysis, data interpretation, and manuscript production.

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Correspondence to Kory J. Lavine.

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Bajpai, G., Schneider, C., Wong, N. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat Med 24, 1234–1245 (2018). https://doi.org/10.1038/s41591-018-0059-x

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