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

Ping-xia Zhang, Jijun Cheng, Siying Zou, Anthony D. D'Souza, Jonathan L. Koff, Jun Lu, Patty J. Lee, Diane S. Krause, Marie E. Egan and Emanuela M. Bruscia ()
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Ping-xia Zhang: Yale University School of Medicine
Jijun Cheng: Yale University School of Medicine
Siying Zou: Yale University School of Medicine
Anthony D. D'Souza: Yale University School of Medicine
Jonathan L. Koff: Critical Care and Sleep Medicine, Yale University School of Medicine
Jun Lu: Yale University School of Medicine
Patty J. Lee: Critical Care and Sleep Medicine, Yale University School of Medicine
Diane S. Krause: Yale University School of Medicine
Marie E. Egan: Yale University School of Medicine
Emanuela M. Bruscia: Yale University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7221

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