Myeloid cell derived Interleukin-6 induces vascular dysfunction and vascular and systemic inflammation

Abstract

The cytokine interleukin-6 (IL-6) plays a central role in the inflammation cascade as well as in 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. IL-6 overexpressing (IL-6OE) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6OE mice) overexpressing the cytokine in myeloid cells. Eight to 12 week old LysM-IL-6OE mice spontaneously developed inflammatory colitis, 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 of vascular smooth muscle cells. In addition to elevated Mcp1 and Cxcl1 mRNA levels, aortae from LysM-IL-6OE mice expressed higher levels of iNOS and endothelin-1, thus partially accounting for vascular dysfunction whereas systemic blood pressure alterations were not observed. Bone marrow transplantation experiments revealed that vascular dysfunction and ROS formation were driven by bone marrow cell-derived IL-6 in a dose-dependent manner. Mice with conditional overexpression of IL-6 in myeloid cells show systemic and vascular inflammation as well as endothelial dysfunction. Decrease of circulating IL-6 levels by replacing IL-6 producing myeloid cells in the bone marrow improved vascular dysfunction in this model, underpinning the relevant role of IL-6 in vascular disease.