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Immunoregulatory Endothelial Cells Interact With T Cells After Myocardial Infarction

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Název: Immunoregulatory Endothelial Cells Interact With T Cells After Myocardial Infarction
Autoři: Lukas S. Tombor, Till Lautenschläger, Simone F. Glaser, Ariane Fischer, Maximilian Merten, Susanne S. Hille, Oliver J. Müller, Christian Kupatt, Tarik Bozoglu, Christoph Kugler, Haider Sami, Manfred Ogris, Kathrin A. Stilz, Josefine Panthel, Marion Muhly-Reinholz, Lisa-Maria Kettenhausen, Lukas Zanders, Leonie Stein, Paul Kiessling, Florian Sicklinger, Florian Leuschner, Bianca Schuhmacher, Mauro Siragusa, David Rodriguez Morales, David John, Haris Kujundzic, Minh-Thuy Katschke, Emmanouil G. Solomonidis, Guillermo Luxán, Stephanie Hehlgans, Franz Rödel, Christoph Kuppe, Wesley T. Abplanalp, Sebastian Cremer, Stefanie Dimmeler
Zdroj: Circulation Research. 137:866-879
Informace o vydavateli: Ovid Technologies (Wolters Kluwer Health), 2025.
Rok vydání: 2025
Témata: Male, 210002 Nanobiotechnologie, Cells, Knockout, infarction, Cell Communication, ischemia, Inbred C57BL, 301207 Pharmazeutische Chemie, Mice, 210002 Nanobiotechnology, Animals, 304004 Gentherapie, T-lymphocytes, 304004 Gene therapy, Cultured, Animal, Core Binding Factor Alpha 2 Subunit/metabolism, Cytokines/metabolism, Endothelial Cells/immunology, T-Lymphocytes/immunology, endothelial cells, inflammation, Disease Models, Myocardial Infarction/immunology, 301207 Pharmaceutical chemistry
Popis: BACKGROUND: Endothelial cells (ECs) play pivotal roles in maintaining cardiac blood supply and regulating inflammation by acting as gatekeepers for immune cell activity. This study unveils a novel immunomodulatory function of cardiac ECs following myocardial infarction. METHODS: We used single-cell RNA sequencing and spatial transcriptomics to identify EC states after acute myocardial infarction in mice. Subsequently, we mimicked the cytokine environment that was predicted to induce EC activation in cell culture studies and confirmed the results in an endothelial-specific deletion mouse model. RESULTS: Single-cell RNA sequencing analysis identified a transient myeloid CD45 + CD11b + Cdh5 + immunomodulatory EC phenotype (IMEC) emerging between days 1 and 3 after myocardial infarction. IMECs derived from Cdh5 + tissue resident cells as shown by bone marrow transplantation and lineage tracing experiment. Ligand-receptor interaction predictions indicated a cytokine-mediated activation of IMECs, which we validated through in vitro experiments in cultured ECs. Notably, while cytokine treatment with IL-1β and TGF-β (transforming growth factor β) induced mesenchymal gene expression, the addition of IFN-γ (interferon γ) facilitated the transition into the immunomodulatory phenotype. IMECs exhibited an upregulation of MHC-II (major histocompatibility complex class II) genes, along with the expression of RUNX1 (runt-related transcription factor-1) and proinflammatory cytokines, such as IL-6 and IL-12. IMECs induced T-cell activation through paracrine signaling and were colocalized with T cells in vivo. Inhibition of endothelial-specific IFN-γ-signaling in mice by IFN-γ receptor 1 deletion improved the recovery after myocardial infarction. CONCLUSIONS: These findings provide insight into the role of ECs regulating adaptive immune responses following myocardial infarction, offering potential insights into therapeutic interventions for postinfarction immunomodulation.
Druh dokumentu: Article
Jazyk: English
ISSN: 1524-4571
0009-7330
DOI: 10.1161/circresaha.125.326145
Rights: CC BY NC ND
Přístupové číslo: edsair.doi.dedup.....6ae1e4a993288aede61e7732cc738dc8
Databáze: OpenAIRE
Popis
Abstrakt:BACKGROUND: Endothelial cells (ECs) play pivotal roles in maintaining cardiac blood supply and regulating inflammation by acting as gatekeepers for immune cell activity. This study unveils a novel immunomodulatory function of cardiac ECs following myocardial infarction. METHODS: We used single-cell RNA sequencing and spatial transcriptomics to identify EC states after acute myocardial infarction in mice. Subsequently, we mimicked the cytokine environment that was predicted to induce EC activation in cell culture studies and confirmed the results in an endothelial-specific deletion mouse model. RESULTS: Single-cell RNA sequencing analysis identified a transient myeloid CD45 + CD11b + Cdh5 + immunomodulatory EC phenotype (IMEC) emerging between days 1 and 3 after myocardial infarction. IMECs derived from Cdh5 + tissue resident cells as shown by bone marrow transplantation and lineage tracing experiment. Ligand-receptor interaction predictions indicated a cytokine-mediated activation of IMECs, which we validated through in vitro experiments in cultured ECs. Notably, while cytokine treatment with IL-1β and TGF-β (transforming growth factor β) induced mesenchymal gene expression, the addition of IFN-γ (interferon γ) facilitated the transition into the immunomodulatory phenotype. IMECs exhibited an upregulation of MHC-II (major histocompatibility complex class II) genes, along with the expression of RUNX1 (runt-related transcription factor-1) and proinflammatory cytokines, such as IL-6 and IL-12. IMECs induced T-cell activation through paracrine signaling and were colocalized with T cells in vivo. Inhibition of endothelial-specific IFN-γ-signaling in mice by IFN-γ receptor 1 deletion improved the recovery after myocardial infarction. CONCLUSIONS: These findings provide insight into the role of ECs regulating adaptive immune responses following myocardial infarction, offering potential insights into therapeutic interventions for postinfarction immunomodulation.
ISSN:15244571
00097330
DOI:10.1161/circresaha.125.326145