Michael Horckmans1, Mariaelvy Bianchini2, Donato Santovito2, Remco T A Megens2,3, Jean-Yves Springael1, Irene Negri1, Michele Vacca4,5,6, Marco Di Eusanio7,8,9, Antonio Moschetta10, Christian Weber2,11,12, Johan Duchene2, Sabine Steffens13,12. 1. Brussels, Belgium (M.H., J.-Y.S., I.N.). 2. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (M.B., D.S., R.T.A.M., C.W., J.D., S.S.). 3. Department of Biomedical Engineering (R.T.A.M.). 4. Cardiovascular Research Institute Maastricht, Maastricht University, Netherlands. Department of Interdisciplinary Medicine (M.V.). 5. University of Bari "Aldo Moro," Italy. Ageing Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy (M.V.). 6. University of Cambridge, United Kingdom (M.V.). 7. Cardiovascular Department, "S.Orsola Malpighi" Hospital, University of Bologna, Italy (M.D.E.). 8. Cardiac Surgery Unit, Ospedali Riuniti of Ancona, Italy (M.D.E.). 9. Cardiac Surgery Department, Ospedali Riuniti "Umberto I-Lancisi-Salesi," Ancona, Italy (M.D.E.). 10. Clinica Medica "C. Frugoni," (A.M.). 11. Department of Biochemistry (C.W.). 12. German Center for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C.W., S.S.). 13. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (M.B., D.S., R.T.A.M., C.W., J.D., S.S.). sabine.steffens@med.uni-muenchen.de.
Abstract
BACKGROUND: The pericardial adipose tissue (AT) contains a high density of lymphoid clusters. It is unknown whether these clusters play a role in post-myocardial infarction (MI) inflammatory responses and cardiac outcome. METHODS: Lymphoid clusters were examined in epicardial AT of humans with or without coronary artery disease. Murine pericardial lymphoid clusters were visualized in mice subjected to coronary artery ligation. To study the relevance of pericardial clusters during inflammatory responses after MI, we surgically removed the pericardial AT and performed B-cell depletion and granulocyte-macrophage colony-stimulating factor blockade. Leukocytes in murine hearts, pericardial AT, spleen, mediastinal lymph nodes, and bone marrow were quantified by flow cytometry. Cannabinoid receptor CB2 (CB2-/-) mice were used as a model for enhanced B-cell responses. The effect of impaired dendritic cell (DC) trafficking on pericardial AT inflammatory responses was tested in CCR7-/- mice subjected to MI. Cardiac fibrosis and ventricular function were assessed by histology and echocardiography. RESULTS: We identified larger B-cell clusters in epicardial AT of human patients with coronary artery disease in comparison with controls without coronary artery disease. Infarcted mice also had larger pericardial clusters and 3-fold upregulated numbers of granulocyte-macrophage colony-stimulating factor-producing B cells within pericardial AT, but not spleen or lymph nodes. This was associated with higher DC and T-cell counts in pericardial AT, which outnumbered DCs and T cells in lymph nodes. Analysis of DC maturation markers, tracking experiments with fluorescently labeled cells, and use of CCR7-deficient mice suggested that activated DCs migrate from infarcts into pericardial AT via CCR7. B-cell depletion or granulocyte-macrophage colony-stimulating factor neutralization inhibited DC and T-cell expansion within pericardial AT, and translated into reduced bone marrow granulopoiesis and cardiac neutrophil infiltration 3 days after MI. The relevance of the pericardial AT in mediating all these effects was confirmed by removal of pericardial AT and ex vivo coculture with pericardial AT and granulocyte progenitors. Finally, enhanced fibrosis and worsened ejection fraction in CB2-/- mice were limited by pericardial AT removal. CONCLUSIONS: Our findings unveil a new mechanism by which the pericardial AT coordinates immune cell activation, granulopoiesis, and outcome after MI.
BACKGROUND: The pericardial adipose tissue (AT) contains a high density of lymphoid clusters. It is unknown whether these clusters play a role in post-myocardial infarction (MI) inflammatory responses and cardiac outcome. METHODS:Lymphoid clusters were examined in epicardial AT of humans with or without coronary artery disease. Murinepericardial lymphoid clusters were visualized in mice subjected to coronary artery ligation. To study the relevance of pericardial clusters during inflammatory responses after MI, we surgically removed the pericardial AT and performed B-cell depletion and granulocyte-macrophage colony-stimulating factor blockade. Leukocytes in murine hearts, pericardial AT, spleen, mediastinal lymph nodes, and bone marrow were quantified by flow cytometry. Cannabinoid receptor CB2 (CB2-/-) mice were used as a model for enhanced B-cell responses. The effect of impaired dendritic cell (DC) trafficking on pericardial AT inflammatory responses was tested in CCR7-/- mice subjected to MI. Cardiac fibrosis and ventricular function were assessed by histology and echocardiography. RESULTS: We identified larger B-cell clusters in epicardial AT of humanpatients with coronary artery disease in comparison with controls without coronary artery disease. Infarcted mice also had larger pericardial clusters and 3-fold upregulated numbers of granulocyte-macrophage colony-stimulating factor-producing B cells within pericardial AT, but not spleen or lymph nodes. This was associated with higher DC and T-cell counts in pericardial AT, which outnumbered DCs and T cells in lymph nodes. Analysis of DC maturation markers, tracking experiments with fluorescently labeled cells, and use of CCR7-deficient mice suggested that activated DCs migrate from infarcts into pericardial AT via CCR7. B-cell depletion or granulocyte-macrophage colony-stimulating factor neutralization inhibited DC and T-cell expansion within pericardial AT, and translated into reduced bone marrow granulopoiesis and cardiac neutrophil infiltration 3 days after MI. The relevance of the pericardial AT in mediating all these effects was confirmed by removal of pericardial AT and ex vivo coculture with pericardial AT and granulocyte progenitors. Finally, enhanced fibrosis and worsened ejection fraction in CB2-/- mice were limited by pericardial AT removal. CONCLUSIONS: Our findings unveil a new mechanism by which the pericardial AT coordinates immune cell activation, granulopoiesis, and outcome after MI.
Authors: Luigi Adamo; Lora J Staloch; Cibele Rocha-Resende; Scot J Matkovich; Wenlong Jiang; Geetika Bajpai; Carla J Weinheimer; Attila Kovacs; Joel D Schilling; Philip M Barger; Deepta Bhattacharya; Douglas L Mann Journal: JCI Insight Date: 2018-06-07
Authors: Ioanna Andreadou; Hector A Cabrera-Fuentes; Yvan Devaux; Nikolaos G Frangogiannis; Stefan Frantz; Tomasz Guzik; Elisa A Liehn; Clarissa P C Gomes; Rainer Schulz; Derek J Hausenloy Journal: Cardiovasc Res Date: 2019-06-01 Impact factor: 10.787
Authors: Luigi Adamo; Cibele Rocha-Resende; Chieh-Yu Lin; Sarah Evans; Jesse Williams; Hao Dun; Wenjun Li; Cedric Mpoy; Prabhakar S Andhey; Buck E Rogers; Kory Lavine; Daniel Kreisel; Maxim Artyomov; Gwendalyn J Randolph; Douglas L Mann Journal: JCI Insight Date: 2020-02-13