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

Macrophages (MFs) 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 MF activation. Because PI3K/AKT signaling is critical for immune regulation, Ezrin-deficient MFs are hyperinflammatory and have impaired Pseudomonas aeruginosa phagocytosis, phenocopying CF MFs. Importantly, we show that activated CF MFs 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.