MicroRNA-181b regulates NF-κB–mediated vascular inflammation
Xinghui Sun, … , Rebecca M. Baron, Mark W. Feinberg
Xinghui Sun, … , Rebecca M. Baron, Mark W. Feinberg
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):1973-1990. https://doi.org/10.1172/JCI61495.
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MicroRNA-181b regulates NF-κB–mediated vascular inflammation

Abstract

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.

Authors

Xinghui Sun, Basak Icli, Akm Khyrul Wara, Nathan Belkin, Shaolin He, Lester Kobzik, Gary M. Hunninghake, Miguel Pinilla Vera, Timothy S. Blackwell, Rebecca M. Baron, Mark W. Feinberg

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Figure 6

miR-181b reduces EC activation and leukocyte accumulation in LPS-induced lung inflammation/injury.

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miR-181b reduces EC activation and leukocyte accumulation in LPS-induced...
(A) Mice were i.v. injected with vehicle, miRNA negative control, or miR-181b mimics and treated with or without LPS (40 mg/kg, i.p., serotype 026:B6) for 4 hours; lungs were harvested and stained for H&E, Gr-1, CD45, or VCAM-1 staining. Scale bars: 50 μm (insets, 20 μm). (B) Evaluation of lung injury 4 hours after LPS was determined by lung injury scoring. Each data point represents score from 1 section. n = 4 mice per group, and 3 sections per mouse were scored. *P < 0.05. (C) Quantification of CD45-positive cells. *P < 0.05. (D) Quantification of Gr-1 positive cells. *P < 0.05. (E) Quantification of VCAM-1 expression. *P < 0.05. n = 4 mice per group; values represent mean ± SD (C–E). (F) Mice were treated as in A. Lungs were harvested and assessed for MPO activity, and the value of the vehicle group was set to 1. Values represent mean ± SD, n = 6 mice per group. (G and H) Mice were treated as in A, and lungs were harvested for Gr-1 staining. Scale bars: 20 μm. Quantification shows the number of Gr-1–positive cells per mm vessel length. Values represent mean ± SD, n = 4. *P < 0.05. (I) Kaplan-Meier survival curves of: LPS-treated C57BL/6 mice (50 mg per kg, i.p., n = 10 to 11 per group) that were injected i.v. with vehicle (black circles), miRNA negative control (red squares), or miR-181b mimics (blue triangles) 48 hours before, 24 hours before, and 1.5 hours after LPS administration. *P < 0.05, 1-tailed log-rank test.