Stefanie Finger1,2,3, Maike Knorr1,2, Michael Molitor1,2,3, Rebecca Schüler1,2,4, Venkata Garlapati2,3, Ari Waisman4, Moritz Brandt1,2, Thomas Münzel1,2,3, Tobias Bopp5, Sabine Kossmann1,2,6, Susanne Karbach1,2,3, Philip Wenzel1,2,3. 1. Center for Cardiology-Cardiology I, University Medical Center Mainz, Langenbeckstraße 1, Mainz, Germany. 2. Center for Thrombosis and Hemostasis, University Medical Center Mainz, Langenbeckstraße 1, Mainz, Germany. 3. German Center for Cardiovascular Research (DZHK)-Partner site RheinMain, University Medical Center Mainz, Langenbeckstraße 1, Mainz, Germany. 4. Institute for Molecular Medicine, University Medical Center Mainz, Langenbeckstraße 1, Mainz, Germany. 5. Institute for Immunology, University Medical Center Mainz, Langenbeckstraße, 1, Mainz, Germany. 6. The Heart Research Institute, 7 Eliza Street, Newtown, NSW, Australia.
Abstract
AIMS: Myelomonocytic cells are critical in injury and healing post-myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-γ) in the orchestrated inflammatory response in a murine model of MI. METHODS AND RESULTS: MI was induced in 8- to 12-week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending (LAD) coronary artery. Lysozyme M (LysM)+ cell-depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1 day post-MI compared with infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-γ and tumour necrosis factor alpha (TNF-α). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28 days post-MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-γ mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1, and Il12b mRNA were reduced 3 days after MI, as was the amount of CD11b+/Ly-6G-/Ly-6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFNγ-/- and TNFα-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-γ impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-γ receptor deficient mice indicated a direct effect of IFN-γ on LysM+ cells in cardiac injury post-MI. Using IFN-γ reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post-MI. CONCLUSION: IFN-γ directs a sequential chemotactic cellular immune response and determines survival and cardiac function post-MI. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Myelomonocytic cells are critical in injury and healing post-myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-γ) in the orchestrated inflammatory response in a murine model of MI. METHODS AND RESULTS: MI was induced in 8- to 12-week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending (LAD) coronary artery. Lysozyme M (LysM)+ cell-depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1 day post-MI compared with infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-γ and tumour necrosis factor alpha (TNF-α). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28 days post-MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-γ mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1, and Il12b mRNA were reduced 3 days after MI, as was the amount of CD11b+/Ly-6G-/Ly-6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFNγ-/- and TNFα-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-γ impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-γ receptor deficient mice indicated a direct effect of IFN-γ on LysM+ cells in cardiac injury post-MI. Using IFN-γ reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post-MI. CONCLUSION: IFN-γ directs a sequential chemotactic cellular immune response and determines survival and cardiac function post-MI. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Tina B Marvasti; Faisal J Alibhai; Lukasz Wlodarek; Anne Fu; Shu-Hong Li; Jun Wu; Richard D Weisel; Robert J Cusimano; Maral Ouzounian; Terrence Yau; Ren-Ke Li Journal: Aging Cell Date: 2021-10-06 Impact factor: 9.304
Authors: Wolf-Stephan Rudi; Michael Molitor; Venkata Garlapati; Stefanie Finger; Johannes Wild; Thomas Münzel; Susanne H Karbach; Philip Wenzel Journal: Antioxidants (Basel) Date: 2021-03-05