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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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).
The authors declare no competing interests.
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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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