Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Knopp T

PROVIDER: S-EPMC11250217 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Knopp Tanja T Jung Rebecca R Wild Johannes J Bochenek Magdalena L ML Efentakis Panagiotis P Lehmann Annika A Bieler Tabea T Garlapati Venkata V Richter Cindy C Molitor Michael M Perius Katharina K Finger Stefanie S Lagrange Jérémy J Ghasemi Iman I Zifkos Konstantinos K Kommoss Katharina S KS Masri Joumana J Reißig Sonja S Randriamboavonjy Voahanginirina V Wunderlich Thomas T Hövelmeyer Nadine N Weber Alexander N R ANR Mufazalov Ilgiz A IA Bosmann Markus M Bechmann Ingo I Fleming Ingrid I Oelze Matthias M Daiber Andreas A Münzel Thomas T Schäfer Katrin K Wenzel Philip P Waisman Ari A Karbach Susanne S

European heart journal open 20240612 4

<h4>Aims</h4>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.<h4>Methods and results</h4>Interleukin-6-overexpressing (IL-6<sup>OE</sup>) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6<sup>OE</sup> mice) overexpressing the ...[more]

PMID: 39015379

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Dataset Information

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

Aims

Methods and results

Conclusion

Publications

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

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