Myeloid cell-derived interleukin-6 induces vascular dysfunction and vascular and systemic inflammation.

Autor:	Knopp T; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Jung R; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Wild J; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany., Bochenek ML; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany., Efentakis P; Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece., Lehmann A; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Bieler T; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Garlapati V; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Richter C; Institute of Anatomy, University Medical Center Leipzig, Leipzig, Germany.; Institute of Neuroradiology, University Medical Center, Leipzig, Germany., Molitor M; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany., Perius K; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Finger S; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Lagrange J; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Ghasemi I; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Zifkos K; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Kommoss KS; Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany., Masri J; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Reißig S; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Randriamboavonjy V; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany., Wunderlich T; Max Planck Institute for Metabolism Research Cologne, Cologne, Germany., Hövelmeyer N; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany.; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Weber ANR; Department of Innate Immunity, Eberhard Karls University Tübingen, Tübingen, Germany., Mufazalov IA; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Bosmann M; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Department of Medicine, Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA., Bechmann I; Institute of Anatomy, University Medical Center Leipzig, Leipzig, Germany., Fleming I; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany.; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany., Oelze M; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Daiber A; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Münzel T; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany., Schäfer K; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany., Wenzel P; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany., Waisman A; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany.; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Karbach S; Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Rhine-Main, Germany.
Jazyk:	angličtina
Zdroj:	European heart journal open [Eur Heart J Open] 2024 Jun 12; Vol. 4 (4), pp. oeae046. Date of Electronic Publication: 2024 Jun 12 (Print Publication: 2024).
DOI:	10.1093/ehjopen/oeae046
Abstrakt:	Aims: The cytokine interleukin-6 (IL-6) plays a central role in the inflammation cascade as well as cardiovascular disease progression. Since myeloid cells are a primary source of IL-6 formation, we aimed to generate a mouse model to study the role of myeloid cell-derived IL-6 in vascular disease. Methods and Results: Interleukin-6-overexpressing (IL-6 OE ) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6 OE mice) overexpressing the cytokine in myeloid cells. Eight- to 12-week-old LysM-IL-6 OE mice spontaneously developed inflammatory colitis and significantly impaired endothelium-dependent aortic relaxation, increased aortic reactive oxygen species (ROS) formation, and vascular dysfunction in resistance vessels. The latter phenotype was associated with decreased survival. Vascular dysfunction was accompanied by a significant accumulation of neutrophils, monocytes, and macrophages in the aorta, increased myeloid cell reactivity (elevated ROS production), and vascular fibrosis associated with phenotypic changes in vascular smooth muscle cells. In addition to elevated Mcp1 and Cxcl1 mRNA levels, aortae from LysM-IL-6 OE mice expressed higher levels of inducible NO synthase and endothelin-1, thus partially accounting for vascular dysfunction, whereas systemic blood pressure alterations were not observed. Bone marrow (BM) transplantation experiments revealed that vascular dysfunction and ROS formation were driven by BM cell-derived IL-6 in a dose-dependent manner. Conclusion: Mice with conditional overexpression of IL-6 in myeloid cells show systemic and vascular inflammation as well as endothelial dysfunction. A decrease in circulating IL-6 levels by replacing IL-6-producing myeloid cells in the BM improved vascular dysfunction in this model, underpinning the relevant role of IL-6 in vascular disease. Competing Interests: Conflict of interest: M.B. received funding and is a consultant for ARCA Biopharma (not related to the presented work). S.K. received funding for consultant lectures from Almiral and Jansson-Cilag (not related to the presented work either). (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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