title: Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation.
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.
authors: 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.
authors: Ping-Xia
authors: PX
authors: Zhang
authors: 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.
authors: Jijun
authors: J
authors: Cheng
authors: Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
authors: Siying
authors: S
authors: Zou
authors: Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
authors: Anthony D
authors: AD
authors: D'Souza
authors: Department of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
authors: Jonathan L
authors: JL
authors: Koff
authors: 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.
authors: Jun
authors: J
authors: Lu
authors: Department of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
authors: Patty J
authors: PJ
authors: Lee
authors: 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.
authors: Diane S
authors: DS
authors: Krause
authors: 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.
authors: Marie E
authors: ME
authors: Egan
authors: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
authors: Emanuela M
authors: EM
authors: Bruscia
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D000068579:Celecoxib / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008168:Lung / Q000201:enzymology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D051197:Toll-Like Receptor 4; C531408:mirn199 microRNA, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib