Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Commun. 2015 Feb 10;6:6221. doi: 10.1038/ncomms7221.

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

Author information

1
1] Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA [2] Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
2
1] Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA [2] Yale Stem Cell Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA [3] Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
3
Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
4
Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
5
Department of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
6
1] Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA [2] Yale Stem Cell Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA [3] Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA [4] Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
7
1] Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA [2] Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
8
Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.

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.

PMID:
25665524
PMCID:
PMC4324503
DOI:
10.1038/ncomms7221
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center