Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload–Driven Heart Failure Reveals Extent of Immune Activation
-
- Elisa Martini
- Adaptive Immunity Laboratory (E.M., M.C., M.K.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Paolo Kunderfranco
- Bioinformatics Unit (P.K., R.C., A.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Clelia Peano
- Genomic Unit (C. Peano, J.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Pierluigi Carullo
- Department of Cardiovascular Medicine (P.C., C. Panico, C. Pagiatakis, G.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Marco Cremonesi
- Adaptive Immunity Laboratory (E.M., M.C., M.K.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Tilo Schorn
- Advanced Imaging Unit (T.S.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Roberta Carriero
- Bioinformatics Unit (P.K., R.C., A.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Alberto Termanini
- Bioinformatics Unit (P.K., R.C., A.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Federico Simone Colombo
- Flow Cytometry Core (F.S.C., E.L.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Elena Jachetti
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (E.J., M.P.C.).
-
- Cristina Panico
- Department of Cardiovascular Medicine (P.C., C. Panico, C. Pagiatakis, G.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Giuseppe Faggian
- Department of Cardiac Surgery, University of Verona, Italy (G.F.).
-
- Andrea Fumero
- Cardiac Surgery Division, Department of Cardiovascular Medicine (A.F., L.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Lucia Torracca
- Cardiac Surgery Division, Department of Cardiovascular Medicine (A.F., L.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Martina Molgora
- Laboratory of Experimental Immunopathology (M.M.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Javier Cibella
- Genomic Unit (C. Peano, J.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Christina Pagiatakis
- Department of Cardiovascular Medicine (P.C., C. Panico, C. Pagiatakis, G.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Jolanda Brummelman
- Laboratory of Translational Immunology (J.B., G.A., E.M.C., E.L.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Giorgia Alvisi
- Laboratory of Translational Immunology (J.B., G.A., E.M.C., E.L.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Emilia Maria Cristina Mazza
- Laboratory of Translational Immunology (J.B., G.A., E.M.C., E.L.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Mario Paolo Colombo
- Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (E.J., M.P.C.).
-
- Enrico Lugli
- Flow Cytometry Core (F.S.C., E.L.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Gianluigi Condorelli
- Department of Cardiovascular Medicine (P.C., C. Panico, C. Pagiatakis, G.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
-
- Marinos Kallikourdis
- Adaptive Immunity Laboratory (E.M., M.C., M.K.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
抄録
<jats:sec> <jats:title>Background:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> 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 <jats:sup>+</jats:sup> 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. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>
収録刊行物
-
- Circulation
-
Circulation 140 (25), 2089-2107, 2019-12-17
Ovid Technologies (Wolters Kluwer Health)