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Nat Immunol. 2019 Jan;20(1):29-39. doi: 10.1038/s41590-018-0272-2. Epub 2018 Dec 11.

Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.

Author information

1
Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Canada.
2
Ted Rogers Centre for Heart Research, Toronto, Canada.
3
Department of Medicine, University of Toronto, Toronto, Canada.
4
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
5
Singapore Immunology Network(SIgN), Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
6
Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
7
Department of Immunology, University of Toronto, Toronto, Canada.
8
Division of Cardiology, Washington University School of Medicine, St Louis, MO, USA.
9
John Cochran VA Medical Center, St Louis, MO, USA.
10
Peter Munk Cardiac Centre, Toronto, Canada.
11
Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Canada. slava.epelman@uhn.ca.
12
Ted Rogers Centre for Heart Research, Toronto, Canada. slava.epelman@uhn.ca.
13
Department of Medicine, University of Toronto, Toronto, Canada. slava.epelman@uhn.ca.
14
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. slava.epelman@uhn.ca.
15
Department of Immunology, University of Toronto, Toronto, Canada. slava.epelman@uhn.ca.
16
Peter Munk Cardiac Centre, Toronto, Canada. slava.epelman@uhn.ca.

Abstract

Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4+LYVE1+MHC-IIloCCR2- resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4-LYVE1-MHC-IIhiCCR2- macrophages and fully replaced TIMD4-LYVE1-MHC-IIhiCCR2+ macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4+ and TIMD4- resident macrophage abundance, whereas CCR2+ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.

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PMID:
30538339
PMCID:
PMC6565365
DOI:
10.1038/s41590-018-0272-2
[Indexed for MEDLINE]
Free PMC Article

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