Self-Renewing Resident Cardiac Macrophages Limit Adverse Remodeling Following Myocardial Infarction
Open accessAbstract
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-II lo CCR2- resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4-LYVE1-MHC-II hi CCR2- macrophages and fully replaced TIMD4-LYVE1-MHC-II hi CCR2+ 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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Resident macrophage markers Lyve1, Folr2 and Timd4 were enriched in myeloid clusters 4 and 6, with Lyve1 and Folr2 also marking clusters 0, 2 and 3.
“Expression of the resident macrophage markers15,16 Lyve1, Folr2 and Timd4 were enriched in clusters 4 and 6, with Lyve1 and Folr2 also marking clusters 0, 2 and 3 (Fig. 1J and Extended Data Fig. 1C-E).”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [15]
The Discussion identifies TIMD4 and LYVE1 as resident cardiac macrophage markers. The Results section on recruited cardiac macrophage plasticity lists Folr2 among genes associated with mature macrophages, but does not specifically establish it as a resident marker. The cluster-enrichment pattern is presented as the citing paper’s own figure result, not as a finding attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredResident macrophage loss is immediately followed by a massive influx of pro-inflammatory, monocyte-derived macrophages (CCR2+) recruited from the circulation.
“Their localized loss is immediately followed by a massive influx of pro-inflammatory, monocyte-derived macrophages (CCR2+) recruited from the circulation [8,9,10].”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
The Results section on resident macrophage loss reports a roughly 60% decline in resident macrophages by day 2 after infarction and a predominance of recruited macrophages afterward. The Abstract identifies CCR2 as a marker of recruited macrophages, but the paper does not establish that influx immediately follows resident-cell loss. Its Results also describe recruited macrophages with both inflammatory and reparative pathways, so calling the influx uniformly pro-inflammatory overstates the finding. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn a healthy heart, tissue-resident macrophages (TRMs) including subsets expressing Timd4, Lyve1, and Folr2 (TLF+) constitute approximately 70% of the cardiac immune compartment and maintain tissue homeostasis.
“In a healthy heart, tissue-resident macrophages (TRMs) (including subsets expressing Timd4, Lyve1, and Folr2, collectively termed TLF+) constitute the vast majority (approximately 70%) of the cardiac immune compartment and are responsible for maintaining tissue homeostasis [9].”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
The Results (Single cell analyses reveal unique cardiac macrophage subsets; page unavailable) identify homeostatic pathways in the Timd4 cluster, and the Results (Recruited cardiac macrophage plasticity within infarcted tissue; page unavailable) list Timd4, Lyve1 and Folr2 among resident-macrophage genes. The copy does not establish that resident macrophages make up approximately 70% of the healthy heart’s immune compartment or demonstrate that they maintain homeostasis. Its 70% figure instead describes macrophage loss in the infarct zone after injury. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTissue-resident macrophages (TRMs, CCR2−, TLF+) were rapidly depleted during the early inflammatory phase of EAM, accompanied by a pronounced influx of CCR2+ monocyte-derived macrophages that dominated the immune landscape at peak inflammation.
“Consistent with earlier reports [8,9], we observed a rapid depletion of tissue-resident macrophages (TRMs, CCR2−, TLF+) during the early inflammatory phase of EAM. This loss was accompanied by a pronounced influx of CCR2+ monocyte-derived macrophages, which dominated the immune landscape at peak inflammation.”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMyocarditis is not only a transient inflammatory condition but a highly orchestrated process involving temporally regulated immune-stromal interactions that critically determine disease outcome.
“Our findings support and extend previous observations that myocarditis is not only a transient inflammatory condition but a highly orchestrated process involving temporally regulated immune–stromal interactions that critically determine the outcome of the disease [9,30].”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
The Abstract and Discussion (pages not provided) show that cardiac macrophage populations change after myocardial infarction and that resident macrophages affect healing and cardiac function. They do not establish the claimed temporally regulated immune–stromal interactions in myocarditis, which is a different condition; the only exact mention of myocarditis found is in a reference title. (LLM, conf=0.86)
Experimental — accuracy not yet measured
CCR2+ macrophages have been identified in human failing hearts and associated with adverse remodelling.
“CCR2+ macrophages have been identified in human failing hearts and associated with adverse remodelling [9]”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
The Results section, “Cardiac macrophage heterogeneity in human cardiomyopathy” (page not provided), identifies CCR2+ macrophages in hearts from patients with cardiomyopathies. It does not associate those human macrophages with adverse remodelling; the paper’s adverse-remodelling finding concerns depletion of resident macrophages after infarction in mice. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe coexistence of pro-inflammatory (Mac-rMHCII, Mono-C) and potentially reparative (Mac-ResL, Mac-TLF) macrophage subsets suggests that broad immunosuppression may unintentionally impair resolution processes.
“The coexistence of pro-inflammatory (Mac-rMHCII, Mono-C) and potentially reparative (Mac-ResL, Mac-TLF) macrophage subsets suggests that broad immunosuppression may unintentionally impair resolution processes [9,10,30].”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
The Results (Single cell analyses reveal unique cardiac macrophage subsets; page unavailable) distinguish inflammatory from homeostatic and regenerative macrophage functions. The Discussion (page unavailable) warns that inhibiting monocyte influx could also impair reparative macrophage development, supporting the concern about indiscriminate suppression. The paper does not identify the named Mac-rMHCII, Mono-C, Mac-ResL, and Mac-TLF subsets or directly assess broad immunosuppression. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBroad-spectrum suppression could impair reparative macrophage subsets like Mac-TLF and Mac-ResL, thereby disrupting their contributions to cardiac homeostasis and resolution of injury.
“However, such broad-spectrum suppression could impair reparative macrophage subsets like Mac-TLF and Mac-ResL, thereby disrupting their contributions to cardiac homeostasis and the resolution of injury [9].”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
The Discussion (page unavailable) says depletion of resident cardiac macrophages worsened infarct healing and identifies possible reparative functions involving TIMD4 and LYVE1. The Abstract also reports that non-selective macrophage depletion limits cardiac repair. The paper does not identify subsets called Mac-TLF or Mac-ResL or establish those named subsets’ individual contributions to homeostasis and injury resolution. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn the heart, two main lineages of macrophages with distinct origins and functions are distinguished: tissue-resident macrophages (TRMs; typically CCR2-), predominantly derived from embryonic development, and recruited monocyte-derived macrophages (CCR2+), which infiltrate from the bloodstream in response to injury.
“In the heart, two main lineages of macrophages with distinct origins and functions are distinguished: tissue-resident macrophages (TRMs; typically CCR2-), predominantly derived from embryonic development, and recruited monocyte-derived macrophages (CCR2+), which infiltrate from the bloodstream in response to injury [7,8,9,10].”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
In response to acute injury, the primary resident macrophage population undergoes rapid depletion, declining by roughly 70% in the injury zone within the first few days.
“In response to acute injury, this primary resident population undergoes rapid depletion, declining by roughly 70% in the injury zone within the first few days.”
From Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune Myocarditis. (2026) · cites this paper as [9]
Integrins can potentiate signals from soluble pro-fibrogenic growth factors such as TGF-β1.
“Of key relevance to fibrosis, integrins can also potentiate signals from soluble pro-fibrogenic growth factors such as TGF-β1.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [87]
Integrins can mediate the translation of spatially fixed extracellular signals into changes in cell behavior including adhesion, migration, proliferation, differentiation, and apoptosis.
“integrins can mediate the translation of spatially-fixed extracellular signals into a wide variety of changes in cell behavior including cell adhesion, migration, proliferation, differentiation and apoptosis86,87.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [87]
The pericellular fibrotic matrix is a remarkably dynamic environment that exerts profound influences on cell behavior, and many key cell-cell and cell-matrix interactions that regulate fibrosis are mediated by members of the integrin family.
“The pericellular fibrotic matrix is a remarkably dynamic environment, which exerts profound influences on cell behavior, and many of the key cell–cell and cell–matrix interactions which regulate fibrosis are mediated by members of the integrin family (noncovalent α/β heterodimers from 18 different α subunits and 8 β subunits resulting in 24 known members in humans)86,87.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [87]
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Self-citation
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Fibrosis: from mechanisms to medicines
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Cells of the adult human heart
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Self-citationPathogenic variants damage cell composition and single cell transcription in cardiomyopathies
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Injectable and conductive cardiac patches repair infarcted myocardium in rats and minipigs
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Interactions between Muscle and Bone—Where Physics Meets Biology
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“However, such broad-spectrum suppression could impair reparative macrophage subsets like Mac-https TLF and Mac-ResL, thereby disrupting their contributions to cardiac homeostasis and the resolution of injury [9].”
Influential
- Authors
- Dick, S. A., Macklin, J. A., Nejat, S., Momen, A., Clemente-Casares, X., Althagafi, M. G., Chen, J., Kantores, C., Hosseinzadeh, S., Aronoff, L., Wong, A., Zaman, R., Barbu, I., Besla, R., Lavine, K. J., Razani, B., Ginhoux, F., Husain, M., Cybulsky, M. I., Robbins, C. S., & Epelman, S.
- Affiliations
- University Health Network (CA)
- Agency for Science, Technology and Research (SG)
- Washington University in St. Louis (US)
- Corresponding author
- Epelman, Slava
- ORCID
- Venue
- Nature Immunology
- Published
- 2018-12-11
- Volume
- 20
- Issue
- 1
- Pages
- 29-39
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC6565365
- OpenAlex
- W2902050841
- Cited by
- 883
- References
- 55
- Citations by year
- 2026: 126 · 2025: 123 · 2024: 140 · 2023: 125 · 2022: 103 · 2021: 110 · 2020: 98 · 2019: 57
- FWCI
- 50.88
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-03-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K08HL112826, R01HL138466, R01HL139714, K08HL123519, R01HL125838)
- National Institute of Allergy and Infectious Diseases (R21AI148877)
- 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
- myocardial infarction, cardiac remodeling, monocyte-derived macrophages, TIMD4, LYVE-1, CCR2, macrophage self-renewal, monocyte recruitment, CX3CR1, peri-infarct zone, cardioprotection, fate mapping, single-cell transcriptomics
- MeSH terms
- Cell Self Renewal, CX3C Chemokine Receptor 1, Animals, Histocompatibility Antigens Class II, Cell Differentiation, Macrophages, Membrane Proteins, Mice, Transgenic, Myocardial Infarction, Myocardium, Parabiosis, Cell Lineage, Ventricular Remodeling, Gene Expression Profiling, Membrane Transport Proteins, Vesicular Transport Proteins, Mice, Receptors, CCR2, Single-Cell Analysis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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