Dendritic cell exosome-shuttled miRNA146a regulates exosome-induced endothelial cell inflammation by inhibiting IRAK-1: A feedback control mechanism

Activation of endothelial cells is the first step of atherosclerosis. The current authors have previously reported that exosomes from mature dendritic cells (mDC-exo) participate in endothelial inflammation and atherosclerosis through membrane tumor necrosis factor-alpha mediated the nuclear factor (NF)-kappa B signaling pathway. However, whether mDC-exo shuttled microRNAs (miRNAs/miRs) play a role in endothelial inflammation remains unknown. In this study, mDC-exo were co-cultured with human umbilical vein endothelial cells (HUVECs) and the expression of adhesion molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-Selectin was investigated. Then the expression of miRNAs in DC-exo was explored and the role of miR-146a in endothelial inflammation was investigated. mDC-exos were first demonstrated to increase endothelial expression of adhesion molecules through a quick activation of the NF-kappa B signaling pathway. Then it was demonstrated that HUVECs resistant to a second stimulation after the first stimulation by mDC-exo. A set of miRNAs were targeted and their expression in HUVECs stimulated with mDC-exo was measured. Finally, it was confirmed that mDC-exo shuttles miR-146a into HUVECs and the shuttled miR-146a contributes to protect HUVECs from a second stimulation through inhibiting interleukin-1 receptor-associated kinase. These data suggest a negative feedback loop of inflammation regulation by DC-exo.