Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Interleukin-6 overexpression in myeloid cells drives vascular dysfunction, inflammation and fibrosis

T. Knopp1, J. Rebecca1, E. Panagiotis2, J. Wild3, M. Molitor1, V. S. Garlapati4, M. Bochenek1, J. Lagrange2, J. Masri5, V. Randriamboavonjy6, T. Wunderlich7, N. Hövelmeyer5, A. Daiber8, M. Bosmann2, K. Schäfer3, I. Fleming9, T. Münzel3, P. Wenzel1, A. Waisman5, S. Karbach1
1Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 2Centrum für Thrombose und Hämostase, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 3Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 4Department of Cardiology, University Medical Center Mainz, Mainz; 5Institut für Molekulare Medizin Mainz, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 6Goethe-Universität Frankfurt am Main Universitätsklinikum, Frankfurt am Main; 7Max Planck Institute for Metabolism Research Cologne, Köln; 8Labor für Molekulare Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 9Institut für Vascular Signalling, Universitätsklinikum Frankfurt, Frankfurt am Main;

Objective: Interleukin-6 (IL-6) is one central cytokine in cardiovascular diseases, mainly released by the myeloid cells. Our goal was to analyze the effect of Lysozyme M+ (LysM+) myeloid cell derived IL-6 on the vasculature and on cardiac function in mice.

Approach: We therefore generated a new mouse strain with conditional IL-6 overexpression from the murine ROSA26 locus (IL-6OE mouse strain). Crossing of the IL-6OE mouse strain to the LysM-Cre mouse strain resulted in LysM-IL-6OE mice in which LysM+ myeloid cells specifically overexpress IL-6, which we analyzed for vascular and cardiac function.

Results: LysM-IL-6OE mice showed a severe vascular dysfunction and increased oxidative stress paralleled by a reduced survival. Cardiac function was not altered. We found a clear serum-IL-6 dependent effect on the development of vascular dysfunction and formation of oxidative stress. Vascular dysfunction was accompanied by a significant infiltration of myeloid cells and especially neutrophil granulocytes in the aortic wall. In parallel, there was an increased perivascular fibrosis, accompanied by elevated levels of Cxcl1, Tnf and Rorc in the aortic vessel wall. In response to chronic myeloid cell derived IL-6 exposure, aortic iNOS and Endothelin-1 were upregulated. eNOS expression was increased, whereas eNOS activatory phosphorylation at its activatory site Ser1177 was not found to be changed. Concerning the cellular Ca2+ cycling, phospholamban phosphorylation was found to be decreased in the aortas of the LysM-IL-6OE mice.

Conclusion: Myeloid cell derived IL-6 evoked severe vascular dysfunction orchestrated by vascular inflammation, dysregulated nitric oxide (NO) and possibly also Ca2+ signaling in line with oxidative stress and vascular fibrosis in mice.


Funding: DFG Grant KA4035-1 to Susanne Karbach.