Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation

Nat Commun. 2015 Feb 10;6:6221. doi: 10.1038/ncomms7221.

Abstract

In cystic fibrosis (CF) patients, hyper-inflammation is a key factor in lung destruction and disease morbidity. We have previously demonstrated that macrophages drive the lung hyper-inflammatory response to LPS in CF mice, because of reduced levels of the scaffold protein CAV1 with subsequent uncontrolled TLR4 signalling. Here we show that reduced CAV1 and, consequently, increased TLR4 signalling, in human and murine CF macrophages and murine CF lungs, is caused by high microRNA-199a-5p levels, which are PI3K/AKT-dependent. Downregulation of microRNA-199a-5p or increased AKT signalling restores CAV1 expression and reduces hyper-inflammation in CF macrophages. Importantly, the FDA-approved drug celecoxib re-establishes the AKT/miR-199a-5p/CAV1 axis in CF macrophages, and ameliorates lung hyper-inflammation in Cftr-deficient mice. Thus, we identify the AKT/miR-199a-5p/CAV1 pathway as a regulator of innate immunity, which is dysfunctional in CF macrophages contributing to lung hyper-inflammation. In addition, we found that this pathway can be targeted by celecoxib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caveolin 1 / metabolism*
  • Celecoxib / pharmacology
  • Cystic Fibrosis / enzymology
  • Cystic Fibrosis / pathology*
  • Humans
  • Inflammation / pathology*
  • Lung / enzymology
  • Lung / pathology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Models, Biological
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / metabolism

Substances

  • Caveolin 1
  • MicroRNAs
  • Mirn199 microRNA, mouse
  • Toll-Like Receptor 4
  • mirn199 microRNA, human
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Celecoxib