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Sci Rep. 2017 Sep 7;7(1):10882. doi: 10.1038/s41598-017-11012-7.

Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages.

Author information

1
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
2
Quinnipiac University School of Medicine, Hamden, CT, USA.
3
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
4
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
5
Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
6
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
7
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA. emanuela.bruscia@yale.edu.

Abstract

Macrophages (MΦs) with mutations in cystic fibrosis transmembrane conductance regulator (CFTR) have blunted induction of PI3K/AKT signaling in response to TLR4 activation, leading to hyperinflammation, a hallmark of cystic fibrosis (CF) disease. Here, we show that Ezrin links CFTR and TLR4 signaling, and is necessary for PI3K/AKT signaling induction in response to MΦ activation. Because PI3K/AKT signaling is critical for immune regulation, Ezrin-deficient MΦs are hyperinflammatory and have impaired Pseudomonas aeruginosa phagocytosis, phenocopying CF MΦs. Importantly, we show that activated CF MΦs have reduced protein levels and altered localization of the remaining Ezrin to filopodia that form during activation. In summary, we have described a direct link from CFTR to Ezrin to PI3K/AKT signaling that is disrupted in CF, and thus promotes hyper-inflammation and weakens phagocytosis.

PMID:
28883468
PMCID:
PMC5589856
DOI:
10.1038/s41598-017-11012-7
[Indexed for MEDLINE]
Free PMC Article

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