VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis

J Exp Med. 2013 Sep 23;210(10):1993-2010. doi: 10.1084/jem.20121200. Epub 2013 Sep 16.

Abstract

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Endothelium / metabolism
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Lung / immunology
  • Lung / metabolism
  • Mice
  • MicroRNAs / genetics*
  • P-Selectin / genetics*
  • P-Selectin / metabolism
  • Pneumonia / genetics*
  • Pneumonia / immunology*
  • RNA Interference
  • Receptors, Thrombopoietin / genetics*
  • Receptors, Thrombopoietin / metabolism
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism*
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • Mirn1 microRNA, mouse
  • Mpl protein, mouse
  • P-Selectin
  • Receptors, Thrombopoietin
  • Vascular Endothelial Growth Factor A