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-6^OE mouse strain). Crossing of the IL-6^OE mouse strain to the LysM-Cre mouse strain resulted in LysM-IL-6^OE mice in which LysM⁺ myeloid cells specifically overexpress IL-6, which we analyzed for vascular and cardiac function.

Results: LysM-IL-6^OE 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-6^OE 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.