• Pauline B Van de Weert-van Leeuwen, Marit A Van Meegen, Jennifer J Speirs, D J Pals, Suzan H M Rooijakkers, Cornelis K Van der Ent, Suzanne W J Terheggen-Lagro, Hubertus G M Arets, and Jeffrey M Beekman.
• Department of Pediatric Pulmonology, Cystic Fibrosis Centre, University Medical Center Utrecht, Utrecht, The Netherlands.
• Am. J. Respir. Cell Mol. Biol. 2013 Sep 1; 49 (3): 463-70.

AbstractCystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is characterized by chronic pulmonary infections. The mechanisms underlying chronic infection and inflammation remain incompletely understood. Mutant CFTR in nonepithelial tissues such as immune cells has been suggested to contribute to infection, inflammation, and the resultant lung disease. However, much controversy still exists regarding the intrinsic role of CFTR in immune cells, especially phagocytes. Therefore, we investigated CFTR expression and function in neutrophils and monocytes isolated from human peripheral blood. CFTR function was assessed by comparing non-CF and CF cells, before and after the chemical inhibition of CFTR. We found CFTR protein expression in monocytes, but this expression was limited or undetectable in neutrophils. Furthermore, the phagocytosis and intracellular killing of Pseudomonas aeruginosa was reduced in CF monocytes, and impaired phagocyte effector mechanisms were phenocopied in non-CF monocytes upon the pharmacological inhibition of CFTR. Reduced phagocytosis in CF monocytes relied on the complement-dependent opsonization of Pseudomonas aeruginosa, and was also observed in the context of latex particles labeled with purified C3b. In mechanistic terms, we observed that CFTR function in monocytes is required for the optimal expression of CD11b. We observed no role for CFTR in neutrophil-mediated phagocytosis. These data support an intrinsic role for CFTR in monocytes, and suggest that CFTR-dependent alterations in complement-mediated interactions between Pseudomonas aeruginosa and monocytes may contribute to enhanced susceptibility to infection in patients with CF.

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