Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload-Driven Heart Failure Reveals Extent of Immune Activation

Research output: Contribution to journalArticle

Abstract

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: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45+ 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.

Original languageEnglish
Pages (from-to)2089-2107
Number of pages19
JournalCirculation
Volume140
Issue number25
DOIs
Publication statusPublished - Dec 17 2019

Fingerprint

Heart Failure
Pressure
Mast Cells
Macrophages
Regulatory T-Lymphocytes
Natural Killer Cells
Heart Diseases
Neutrophils
B-Lymphocytes
Oncostatin M
RNA Sequence Analysis
T-Lymphocytes
Pericardium
Immunotherapy
Dendritic Cells
Fluorescent Antibody Technique
Myocardium
Flow Cytometry
Up-Regulation
Tumor Necrosis Factor-alpha

Keywords

  • cardiac failure
  • cardiac toxicity
  • congestive heart failure
  • oncostatin M
  • programmed cell death, type I
  • sequence analysis, RNA

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{1e0c438beb0e465f89bb2e3cc44daef9,
title = "Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload-Driven Heart Failure Reveals Extent of Immune Activation",
abstract = "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: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45+ 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.",
keywords = "cardiac failure, cardiac toxicity, congestive heart failure, oncostatin M, programmed cell death, type I, sequence analysis, RNA",
author = "Elisa Martini and Paolo Kunderfranco and Clelia Peano and Pierluigi Carullo and Marco Cremonesi and Tilo Schorn and Roberta Carriero and Alberto Termanini and Colombo, {Federico Simone} and Elena Jachetti and Cristina Panico and Giuseppe Faggian and Andrea Fumero and Lucia Torracca and Martina Molgora and Javier Cibella and Christina Pagiatakis and Jolanda Brummelman and Giorgia Alvisi and Mazza, {Emilia Maria Cristina} and Colombo, {Mario Paolo} and Enrico Lugli and Gianluigi Condorelli and Marinos Kallikourdis",
year = "2019",
month = "12",
day = "17",
doi = "10.1161/CIRCULATIONAHA.119.041694",
language = "English",
volume = "140",
pages = "2089--2107",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "25",

}

TY - JOUR

T1 - Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload-Driven Heart Failure Reveals Extent of Immune Activation

AU - Martini, Elisa

AU - Kunderfranco, Paolo

AU - Peano, Clelia

AU - Carullo, Pierluigi

AU - Cremonesi, Marco

AU - Schorn, Tilo

AU - Carriero, Roberta

AU - Termanini, Alberto

AU - Colombo, Federico Simone

AU - Jachetti, Elena

AU - Panico, Cristina

AU - Faggian, Giuseppe

AU - Fumero, Andrea

AU - Torracca, Lucia

AU - Molgora, Martina

AU - Cibella, Javier

AU - Pagiatakis, Christina

AU - Brummelman, Jolanda

AU - Alvisi, Giorgia

AU - Mazza, Emilia Maria Cristina

AU - Colombo, Mario Paolo

AU - Lugli, Enrico

AU - Condorelli, Gianluigi

AU - Kallikourdis, Marinos

PY - 2019/12/17

Y1 - 2019/12/17

N2 - 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: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45+ 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.

AB - 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: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45+ 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.

KW - cardiac failure

KW - cardiac toxicity

KW - congestive heart failure

KW - oncostatin M

KW - programmed cell death, type I

KW - sequence analysis, RNA

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U2 - 10.1161/CIRCULATIONAHA.119.041694

DO - 10.1161/CIRCULATIONAHA.119.041694

M3 - Article

C2 - 31661975

AN - SCOPUS:85076162834

VL - 140

SP - 2089

EP - 2107

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 25

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