Cardiac Resident Macrophages Prevent Fibrosis and Stimulate Angiogenesis
Open accessAbstract
Rationale: The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads to heart failure. Recently, a role for recruited macrophages in determining the transition from compensated to decompensated hypertrophy has been established. However, whether cardiac resident immune cells influence the early phase of hypertrophy development has not been established. Objective: To assess the role of cardiac immune cells in the early hypertrophy response to cardiac pressure overload induced by transverse aortic constriction (TAC). Methods and Results: We performed cytometry by time-of-flight to determine the identity and abundance of immune cells in the heart at 1 and 4 weeks after TAC. We observed a substantial increase in cardiac macrophages 1 week after TAC. We then conducted Cite-Seq single-cell RNA sequencing of cardiac immune cells isolated from 4 sham and 6 TAC hearts. We identified 12 clusters of monocytes and macrophages, categorized as either resident or recruited macrophages, that showed remarkable changes in their abundance between sham and TAC conditions. To determine the role of cardiac resident macrophages early in the response to a hypertrophic stimulus, we used a blocking antibody against macrophage colony-stimulating factor 1 receptor (CD115). As blocking CD115 initially depletes all macrophages, we allowed the replenishment of recruited macrophages by monocytes before performing TAC. This preferential depletion of resident macrophages resulted in enhanced fibrosis and a blunted angiogenesis response to TAC. Macrophage depletion in CCR2 (C-C chemokine receptor type 2) knockout mice showed that aggravated fibrosis was primarily caused by the recruitment of monocyte-derived macrophages. Finally, 6 weeks after TAC these early events lead to depressed cardiac function and enhanced fibrosis, despite complete restoration of cardiac immune cells. Conclusions: Cardiac resident macrophages are a heterogeneous population of immune cells with key roles in stimulating angiogenesis and inhibiting fibrosis in response to cardiac pressure overload.
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Flow cytometry at day 7 after TAC showed no significant change in infiltrated immune cell, monocyte or macrophage numbers after JQ1.
“Flow cytometry analyses of cardiac tissue at day 7 post-TAC, a time point associated with immune cell expansion23,24, revealed no significant changes in the number of infiltrated immune cells, monocytes, or macrophages following JQ1 (Extended Data Fig. 1H,I).”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [24]
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Cites
Dimensionality reduction for visualizing single-cell data using UMAP
Becht, E., McInnes, L., Healy, J., Dutertre, C.-A., Kwok, I. W. H., Ng, L. G., Ginhoux, F., & Newell, E. W. (2019) · Nature Biotechnology · doi:10.1038/nbt.4314 · Cited by 5,358 · see citing works
Hafemeister, C., & Satija, R. (2019) · Genome Biology · doi:10.1186/s13059-019-1874-1 · Cited by 4,479 · see citing works
Simultaneous epitope and transcriptome measurement in single cells
Stoeckius, M., Hafemeister, C., Stephenson, W., Houck-Loomis, B., Chattopadhyay, P. K., Swerdlow, H., Satija, R., & Smibert, P. (2017) · Nature Methods · doi:10.1038/nmeth.4380 · Cited by 3,098 · see citing works
Bendall, S. C., Simonds, E. F., Qiu, P., Amir, E.-A. D., Krutzik, P. O., Finck, R., Bruggner, R. V., Melamed, R., Trejo, A., Ornatsky, O. I., et al. (2011) · Science · doi:10.1126/science.1198704 · Cited by 2,279 · see citing works
PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity
Gordon, S. R., Maute, R. L., Dulken, B. W., Hutter, G., George, B. M., McCracken, M. N., Gupta, R., Tsai, J. M., Sinha, R., Corey, D., et al. (2017) · Nature · doi:10.1038/nature22396 · Cited by 2,247 · see citing works
Identification of splenic reservoir monocytes and their deployment to inflammatory sites
Swirski, F. K., Nahrendorf, M., Etzrodt, M., Wildgruber, M., Cortez-Retamozo, V., Panizzi, P., Figueiredo, J.-L., Kohler, R. H., Chudnovskiy, A., Waterman, P., et al. (2009) · Science · doi:10.1126/science.1175202 · Cited by 2,221 · see citing works
Mechanisms of physiological and pathological cardiac hypertrophy
Nakamura, M., & Sadoshima, J. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0007-y · Cited by 1,662 · see citing works
Epelman, S., Lavine, K. J., Beaudin, A. E., Sojka, D. K., Carrero, J. A., Calderon, B., Brija, T., Gautier, E. L., Ivanov, S., Satpathy, A. T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2013.11.019 · Cited by 1,494 · see citing works
Macrophages Facilitate Electrical Conduction in the Heart
Hulsmans, M., Clauss, S., Xiao, L., Aguirre, A. D., King, K. R., Hanley, A., Hucker, W. J., Wülfers, E. M., Seemann, G., Courties, G., et al. (2017) · Cell · doi:10.1016/j.cell.2017.03.050 · Cited by 1,011 · see citing works
p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload
Sano, M., Minamino, T., Toko, H., Miyauchi, H., Orimo, M., Qin, Y., Akazawa, H., Tateno, K., Kayama, Y., Harada, M., et al. (2007) · Nature · doi:10.1038/nature05602 · Cited by 911 · see citing works
Self-Renewing Resident Cardiac Macrophages Limit Adverse Remodeling Following Myocardial Infarction
Dick, S. A., Macklin, J. A., Nejat, S., Momen, A., Clemente-Casares, X., Althagafi, M. G., Chen, J., Kantores, C., Hosseinzadeh, S., Aronoff, L., et al. (2019) · Nature Immunology · doi:10.1038/s41590-018-0272-2 · Cited by 883 · see citing works
Lavine, K. J., Epelman, S., Uchida, K., Weber, K. J., Nichols, C. G., Schilling, J. D., Ornitz, D. M., Randolph, G. J., & Mann, D. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1406508111 · Cited by 818 · see citing works
A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart
Nicolás-Ávila, J. A., Lechuga-Vieco, A. V., Esteban-Martínez, L., Sánchez-Díaz, M., Díaz-García, E., Santiago, D. J., Rubio-Ponce, A., Li, J. L., Balachander, A., Quintana, J. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.031 · Cited by 762 · see citing works
Bajpai, G., Bredemeyer, A., Li, W., Zaitsev, K., Koenig, A. L., Lokshina, I., Mohan, J., Ivey, B., Hsiao, H.-M., Weinheimer, C., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.314028 · Cited by 751 · see citing works
The human heart contains distinct macrophage subsets with divergent origins and functions
Bajpai, G., Schneider, C., Wong, N., Bredemeyer, A., Hulsmans, M., Nahrendorf, M., Epelman, S., Kreisel, D., Liu, Y., Itoh, A., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0059-x · Cited by 712 · see citing works
Transcriptional and Cellular Diversity of the Human Heart
Tucker, N. R., Chaffin, M., Fleming, S. J., Hall, A. W., Parsons, V. A., Bedi, K. C., Akkad, A.-D., Herndon, C. N., Arduini, A., Papangeli, I., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.045401 · Cited by 554 · see citing works
Establishment and Maintenance of the Macrophage Niche
Guilliams, M., Thierry, G. R., Bonnardel, J., & Bajenoff, M. (2020) · Immunity · doi:10.1016/j.immuni.2020.02.015 · Cited by 512 · see citing works
MacDonald, K. P. A., Palmer, J. S., Cronau, S. L., Seppanen, E. J., Olver, S. D., Raffelt, N. C., Kuns, R. D., Pettit, A. R., Clouston, A. D., Wainwright, B. J., et al. (2010) · Blood · doi:10.1182/blood-2010-02-266296 · Cited by 507 · see citing works
Cardiac macrophages promote diastolic dysfunction
Hulsmans, M., Sager, H. B., Roh, J. D., Valero‐Muñoz, M., Houstis, N. E., Iwamoto, Y., Sun, Y., Wilson, R. M., Wojtkiewicz, G. R., Tricot, B., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171274 · Cited by 498 · see citing works
Signaling effectors underlying pathologic growth and remodeling of the heart
van Berlo, J. H., Maillet, M., & Molkentin, J. D. (2013) · Journal of Clinical Investigation · doi:10.1172/jci62839 · Cited by 446 · see citing works
Martini, E., Kunderfranco, P., Peano, C., Carullo, P., Cremonesi, M., Schorn, T., Carriero, R., Termanini, A., Colombo, F. S., Jachetti, E., et al. (2019) · Circulation · doi:10.1161/circulationaha.119.041694 · Cited by 341 · see citing works
Pinto, A. R., Paolicelli, R., Salimova, E., Gospocic, J., Slonimsky, E., Bilbao-Cortes, D., Godwin, J. W., & Rosenthal, N. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036814 · Cited by 318 · see citing works
Gladka, M. M., Molenaar, B., de Ruiter, H., van der Elst, S., Tsui, H., Versteeg, D., Lacraz, G., Huibers, M. M. H., van Oudenaarden, A., & van Rooij, E. (2018) · Circulation · doi:10.1161/circulationaha.117.030742 · Cited by 312 · see citing works
Patel, B., Bansal, S. S., Ismahil, M. A., Hamid, T., Rokosh, G., Mack, M., & Prabhu, S. D. (2018) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2017.12.006 · Cited by 297 · see citing works
Perrino, C. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25397 · Cited by 261 · see citing works
Female sex and estrogen receptor-β attenuate cardiac remodeling and apoptosis in pressure overload
Fliegner, D., Schubert, C., Penkalla, A., Witt, H., Kararigas, G., Dworatzek, E., Staub, E., Martus, P., Ruíz, P., Kintscher, U., et al. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00825.2009 · Cited by 253 · see citing works
Inhibition of Hypertrophy Is a Good Therapeutic Strategy in Ventricular Pressure Overload
Schiattarella, G. G., & Hill, J. A. (2015) · Circulation · doi:10.1161/circulationaha.115.013894 · Cited by 251 · see citing works
Ren, Z., Peng, Y., Li, D., Li, Z., Liao, Y., Wang, Y., Zhou, B., & Wang, L. (2020) · Circulation · doi:10.1161/circulationaha.119.043053 · Cited by 251 · see citing works
Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure
Nevers, T. A., Salvador, A. M., Velazquez, F., Ngwenyama, N., Carrillo-Salinas, F. J., Aronovitz, M. J., Blanton, R. M., & Alcaide, P. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20161791 · Cited by 227 · see citing works
Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy
Liao, X., Shen, Y., Zhang, R., Sugi, K., Vasudevan, N. T., Alaiti, M. A., Sweet, D. R., Zhou, L., Qing, Y., Gerson, S. L., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720065115 · Cited by 185 · see citing works
Gata6+ Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis
Deniset, J. F., Belke, D., Lee, W.-Y., Jorch, S. K., Deppermann, C., Hassanabad, A. F., Turnbull, J. D., Teng, G., Rozich, I., Hudspeth, K., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.06.010 · Cited by 178 · see citing works
Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling
Li, W., Hsiao, H.-M., Higashikubo, R., Saunders, B. T., Bharat, A., Goldstein, D. R., Krupnick, A. S., Gelman, A. E., Lavine, K. J., & Kreisel, D. (2016) · JCI Insight · doi:10.1172/jci.insight.87315 · Cited by 162 · see citing works
CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction
Ngwenyama, N., Salvador, A. M., Velázquez, F., Nevers, T. A., Levy, A. M., Aronovitz, M. J., Luster, A. D., Huggins, G. S., & Alcaide, P. (2019) · JCI Insight · doi:10.1172/jci.insight.125527 · Cited by 96 · see citing works
Verma, S. K., Garikipati, V. N. S., Krishnamurthy, P., Schumacher, S. M., Grisanti, L. A., Cimini, M., Cheng, Z. A., Khan, M., Yue, Y., Benedict, C., et al. (2017) · Circulation · doi:10.1161/circulationaha.117.027889 · Cited by 84 · see citing works
Leukocyte-Expressed β2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury
Grisanti, L. A., Gumpert, A. M., Traynham, C. J., Gorsky, J., Repas, A. A., Gao, E., Carter, R. L., Yu, D., Calvert, J. W., Pun-García, A., et al. (2016) · Circulation · doi:10.1161/circulationaha.116.022304 · Cited by 69 · see citing works
Carlson, S., Helterline, D., Asbe, L., Dupras, S. K., Minami, E., Farris, S. D., & Stempien‐Otero, A. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.05.016 · Cited by 55 · see citing works
Leukocyte-Dependent Regulation of Cardiac Fibrosis
Okyere, A. D., & Tilley, D. G. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00301 · Cited by 43 · see citing works
Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit+Cells
Chen, Z., Zhu, W., Bender, I. K., Gong, W., Kwak, I., Yellamilli, A., Hodges, T. J., Nemoto, N., Zhang, J. J., Garry, D. J., et al. (2017) · Circulation · doi:10.1161/circulationaha.117.030137 · Cited by 24 · see citing works
Abcg2 ‐expressing side population cells contribute to cardiomyocyte renewal through fusion
Yellamilli, A., Ren, Y., McElmurry, R. T., Lambert, J. P., Gross, P., Mohsin, S., Houser, S. R., Elrod, J. W., Tolar, J., Garry, D. J., et al. (2020) · The FASEB Journal · doi:10.1096/fj.201902105r · Cited by 12 · see citing works
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Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure
Koenig, A. L., Shchukina, I., Amrute, J., Andhey, P. S., Zaitsev, K., Lai, L., Bajpai, G., Bredemeyer, A., Smith, G., Jones, C., et al. (2022) · Nature Cardiovascular Research · doi:10.1038/s44161-022-00028-6 · Cited by 482 · see citing works
Chromatin remodelling drives immune cell–fibroblast communication in heart failure
Alexanian, M., Padmanabhan, A., Nishino, T., Travers, J. G., Ye, L., Pelonero, A., Lee, C. Y., Sadagopan, N., Huang, Y., Auclair, K., et al. (2024) · Nature · doi:10.1038/s41586-024-08085-6 · Cited by 140 · see citing works
- Authors
- Revelo, X. S., Parthiban, P., Chen, C., Barrow, F., Fredrickson, G., Wang, H., Yücel, D., Herman, A., & van Berlo, J. H.
- Affiliations
- University of Minnesota (US)
- Department of Integrative Biology and Physiology (X.S.R., P.P., F.B., G.F., H.W., D.Y., J.H.v.B.), University of Minnesota, Minneapolis, MN, 55455.
- Corresponding author
- Revelo, Xavier S.
- Venue
- Circulation Research
- Published
- 2021-12-03
- Volume
- 129
- Issue
- 12
- Pages
- 1086-1101
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC8638822
- OpenAlex
- W3207283439
- Cited by
- 298
- References
- 39
- Citations by year
- 2026: 50 · 2025: 80 · 2024: 89 · 2023: 47 · 2022: 31 · 2021: 1
- FWCI
- 28.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Circulation Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK122056)
- HHS | NIH | National Heart, Lung, and Blood Institute (HL130072, HL155993)
- Hartwell Foundation (NA)
- American Association of Immunologists (NA)
- 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 › Surgery › Transplantation: Methods and Outcomes
- Keywords
- cardiac resident macrophages, cardiac hypertrophy, cardiac pressure overload, transverse aortic constriction, myocardial fibrosis, angiogenesis, monocyte-derived macrophages, macrophage recruitment, CCR2, CD115, heart failure, monocyte heterogeneity
- MeSH terms
- Animals, Cells, Cultured, Fibrosis, Cardiomegaly, Macrophages, Mice, Inbred C57BL, Myocardium, Receptor, Macrophage Colony-Stimulating Factor, Neovascularization, Physiologic, Mice, Receptors, CCR2, Single-Cell Analysis, Transcriptome
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