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Immunoregulatory endothelial cells interact with T cells after myocardial infarction

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...

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Main Authors: Tombor, Lukas (Author) , Lautenschläger, Till (Author) , Glaser, Simone F. (Author) , Fischer, Ariane (Author) , Merten, Maximilian (Author) , Hille, Susanne S. (Author) , Müller, Oliver J. (Author) , Kupatt, Christian (Author) , Bozoglu, Tarik (Author) , Kugler, Christoph (Author) , Sami, Haider (Author) , Ogris, Manfred (Author) , Stilz, Kathrin A. (Author) , Panthel, Josefine (Author) , Muhly-Reinholz, Marion (Author) , Kettenhausen, Lisa-Maria (Author) , Zanders, Lukas (Author) , Stein, Leonie (Author) , Kiessling, Paul (Author) , Sicklinger, Florian (Author) , Leuschner, Florian (Author) , Schuhmacher, Bianca (Author) , Siragusa, Mauro (Author) , Rodriguez Morales, David (Author) , John, David (Author) , Kujundzic, Haris (Author) , Katschke, Minh-Thuy (Author) , Solomonidis, Emmanouil G. (Author) , Luxán, Guillermo (Author) , Hehlgans, Stephanie (Author) , Rödel, Franz (Author) , Kuppe, Christoph (Author) , Abplanalp, Wesley T. (Author) , Cremer, Sebastian (Author) , Dimmeler, Stefanie (Author)
Format: Article (Journal)
Language:English
Published: August 29, 2025
In: Circulation research
Year: 2025, Volume: 137, Issue: 6, Pages: 866-879
ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.125.326145
Online Access:Resolving-System, kostenfrei, Volltext: https://doi.org/10.1161/CIRCRESAHA.125.326145
Verlag, kostenfrei, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.125.326145
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Author Notes: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, and Stefanie Dimmeler
Description
Summary: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.
Item Description:Online veröffentlicht am: 30. Juli 2025
Gesehen am 13.04.2026
Physical Description:Online Resource
ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.125.326145

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