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Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload–Driven Heart Failure Reveals Extent of Immune Activation
Open accessAbstract
BACKGROUND: Inflammation is a key component of cardiac disease, with macrophages and T lymphocytes mediating essential roles in the progression to heart failure. Nonetheless, little insight exists on other immune subsets involved in the cardiotoxic response. METHODS: cells, we obtained a higher resolution identification of the immune cell subsets in the heart, at early and late stages of disease and in controls. We then integrated our findings using multiparameter flow cytometry, immunohistochemistry, and tissue clarification immunofluorescence in mouse and human. RESULTS: We found that most major immune cell subpopulations, including macrophages, B cells, T cells and regulatory T cells, dendritic cells, Natural Killer cells, neutrophils, and mast cells are present in both healthy and diseased hearts. Most cell subsets are found within the myocardium, whereas mast cells are found also in the epicardium. Upon induction of pressure overload, immune activation occurs across the entire range of immune cell types. Activation led to upregulation of key subset-specific molecules, such as oncostatin M in proinflammatory macrophages and PD-1 in regulatory T cells, that may help explain clinical findings such as the refractivity of patients with heart failure to anti-tumor necrosis factor therapy and cardiac toxicity during anti-PD-1 cancer immunotherapy, respectively. CONCLUSIONS: Despite the absence of infectious agents or an autoimmune trigger, induction of disease leads to immune activation that involves far more cell types than previously thought, including neutrophils, B cells, Natural Killer cells, and mast cells. This opens up the field of cardioimmunology to further investigation by using toolkits that have already been developed to study the aforementioned immune subsets. The subset-specific molecules that mediate their activation may thus become useful targets for the diagnostics or therapy of heart failure.
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Metadata
- Authors
- Martini, E., Kunderfranco, P., Peano, C., Carullo, P., Cremonesi, M., Schorn, T., Carriero, R., Termanini, A., Colombo, F. S., Jachetti, E., Panico, C., Faggian, G., Fumero, A., Torracca, L., Molgora, M., Cibella, J., Pagiatakis, C., Brummelman, J., Alvisi, G., Mazza, E. M. C., Colombo, M. P., Lugli, E., Condorelli, G., & Kallikourdis, M.
- Affiliations
- IRCCS Humanitas Research Hospital (IT)
- Institute of Genetic and Biomedical Research (IT)
- Humanitas University (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- University of Verona (IT)
- Cardiac Surgery Division, Department of Cardiovascular Medicine (A.F., L.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
- Fondazione Humanitas per la Ricerca (IT)
- Corresponding author
- Martini, Elisa
- Kunderfranco, Paolo
- ORCID
- Martini, Elisa
- Kunderfranco, Paolo
- Peano, Clelia
- Carullo, Pierluigi
- Cremonesi, Marco
- Schorn, Tilo
- Carriero, Roberta
- Termanini, Alberto
- Colombo, Federico Simone
- Jachetti, Elena
- Panico, Cristina
- Faggian, Giuseppe
- Torracca, Lucia
- Molgora, Martina
- Cibella, Javier
- Pagiatakis, Christina
- Brummelman, Jolanda
- Alvisi, Giorgia
- Mazza, Emilia Maria Cristina
- Colombo, Mario Paolo
- Lugli, Enrico
- Condorelli, Gianluigi
- Kallikourdis, Marinos
- Venue
- Circulation
- Published
- 2019-12-17
- Volume
- 140
- Issue
- 25
- Pages
- 2089-2107
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2982367920
- Cited by
- 341
- References
- 52
- Citations by year
- 2026: 31 · 2025: 56 · 2024: 58 · 2023: 57 · 2022: 57 · 2021: 50 · 2020: 31 · 2019: 1
- FWCI
- 25.11
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- IrInSubria (University of Insubria) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- 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
- heart failure, pressure overload, cardiac inflammation, macrophages, T cells, regulatory T cells, mast cells, neutrophils, natural killer cells, dendritic cells, B cells, oncostatin M, PD-1, epicardium
- MeSH terms
- Animals, B-Lymphocytes, Dendritic Cells, Flow Cytometry, Heart Failure, Humans, Immunity, Cellular, Killer Cells, Natural, Mice, Inbred C57BL, Myocardium, Neutrophils, Sequence Analysis, RNA, Mice, Single-Cell Analysis
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