Elisa Martini1, Paolo Kunderfranco2, Clelia Peano3,4, Pierluigi Carullo5,4, Marco Cremonesi1, Tilo Schorn6, Roberta Carriero2, Alberto Termanini2, Federico Simone Colombo7, Elena Jachetti8, Cristina Panico5, Giuseppe Faggian9, Andrea Fumero10, Lucia Torracca10, Martina Molgora11, Javier Cibella3, Christina Pagiatakis5, Jolanda Brummelman12, Giorgia Alvisi12, Emilia Maria Cristina Mazza12, Mario Paolo Colombo8, Enrico Lugli7,12, Gianluigi Condorelli5,4,13, Marinos Kallikourdis1,13. 1. Adaptive Immunity Laboratory (E.M., M.C., M.K.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 2. Bioinformatics Unit (P.K., R.C., A.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 3. Genomic Unit (C. Peano, J.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 4. Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, Italy (C. Peano, P.C., G.C.). 5. Department of Cardiovascular Medicine (P.C., C. Panico, C. Pagiatakis, G.C.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 6. Advanced Imaging Unit (T.S.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 7. Flow Cytometry Core (F.S.C., E.L.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 8. Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (E.J., M.P.C.). 9. Department of Cardiac Surgery, University of Verona, Italy (G.F.). 10. Cardiac Surgery Division, Department of Cardiovascular Medicine (A.F., L.T.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 11. Laboratory of Experimental Immunopathology (M.M.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 12. Laboratory of Translational Immunology (J.B., G.A., E.M.C., E.L.), Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 13. Humanitas University, Pieve Emanuele, Italy (G.C., M.K.).
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.
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.
Entities:
Keywords:
cardiac failure; cardiac toxicity; congestive heart failure; oncostatin M; programmed cell death, type I; sequence analysis, RNA
Authors: Ernesto Marín-Sedeño; Xabier Martínez de Morentin; Jose M Pérez-Pomares; David Gómez-Cabrero; Adrián Ruiz-Villalba Journal: Front Cell Dev Biol Date: 2021-05-12