MicroRNA-181b regulates NF-κB–mediated vascular inflammation

• Published in: The Journal of clinical investigation Vol. 122; no. 6; pp. 1973 - 1990
• Main Authors: Sun, Xinghui, Icli, Basak, Wara, Akm Khyrul, Belkin, Nathan, He, Shaolin, Kobzik, Lester, Hunninghake, Gary M., Vera, Miguel Pinilla, Blackwell, Timothy S., Baron, Rebecca M., Feinberg, Mark W.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2012
• Subjects: Acute Lung Injury - genetics; Acute Lung Injury - immunology; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Acute Lung Injury - therapy; alpha Karyopherins - genetics; alpha Karyopherins - immunology; alpha Karyopherins - metabolism; Animals; Critical Illness; E-Selectin - genetics; E-Selectin - immunology; E-Selectin - metabolism; Endothelial Cells - immunology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endotoxemia - genetics; Endotoxemia - immunology; Endotoxemia - metabolism; Endotoxemia - pathology; Endotoxemia - therapy; Humans; Leukocytes - immunology; Leukocytes - metabolism; Leukocytes - pathology; Lipopolysaccharides - toxicity; Mice; MicroRNAs - genetics; MicroRNAs - immunology; MicroRNAs - metabolism; NF-kappa B - genetics; NF-kappa B - immunology; NF-kappa B - metabolism; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - immunology; Vascular Cell Adhesion Molecule-1 - metabolism; Vasculitis - genetics; Vasculitis - immunology; Vasculitis - metabolism; Vasculitis - therapy
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI61495

EC activation and dysfunction have been linked to a variety of vascular inflammatory disease states. The function of microRNAs (miRNAs) in vascular EC activation and inflammation remains poorly understood. Herein, we report that microRNA-181b (miR-181b) serves as a potent regulator of downstream NF-κB signaling in the vascular endothelium by targeting importin-α3, a protein that is required for nuclear translocation of NF-κB. Overexpression of miR-181b inhibited importin-α3 expression and an enriched set of NF-κB-responsive genes such as adhesion molecules VCAM-1 and E-selectin in ECs in vitro and in vivo. In addition, treatment of mice with proinflammatory stimuli reduced miR-181b expression. Rescue of miR-181b levels by systemic administration of miR-181b "mimics" reduced downstream NF-κB signaling and leukocyte influx in the vascular endothelium and decreased lung injury and mortality in endotoxemic mice. In contrast, miR-181b inhibition exacerbated endotoxin-induced NF-κB activity, leukocyte influx, and lung injury. Finally, we observed that critically ill patients with sepsis had reduced levels of miR-181b compared with control intensive care unit (ICU) subjects. Collectively, these findings demonstrate that miR-181b regulates NF-κB-mediated EC activation and vascular inflammation in response to proinflammatory stimuli and that rescue of miR-181b expression could provide a new target for antiinflammatory therapy and critical illness.