Disease-causing Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator Determine the Functional Responses of Alveolar Macrophages

Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2009; 284(51):35926-38. DOI: 10.1074/jbc.M109.057372
Source: PubMed


Alveolar macrophages (AMs) play a major role in host defense against microbial infections in the lung. To perform this function, these cells must ingest and destroy pathogens, generally in phagosomes, as well as secrete a number of products that signal other immune cells to respond. Recently, we demonstrated that murine alveolar macrophages employ the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel as a determinant in lysosomal acidification (Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C., and Nelson, D. J. (2006) Nat. Cell Biol. 8, 933-944). Lysosomes and phagosomes in murine cftr(-/-) AMs failed to acidify, and the cells were deficient in bacterial killing compared with wild type controls. Cystic fibrosis is caused by mutations in CFTR and is characterized by chronic lung infections. The information about relationships between the CFTR genotype and the disease phenotype is scarce both on the organismal and cellular level. The most common disease-causing mutation, DeltaF508, is found in 70% of patients with cystic fibrosis. The mutant protein fails to fold properly and is targeted for proteosomal degradation. G551D, the second most common mutation, causes loss of function of the protein at the plasma membrane. In this study, we have investigated the impact of CFTR DeltaF508 and G551D on a set of core intracellular functions, including organellar acidification, granule secretion, and microbicidal activity in the AM. Utilizing primary AMs from wild type, cftr(-/-), as well as mutant mice, we show a tight correlation between CFTR genotype and levels of lysosomal acidification, bacterial killing, and agonist-induced secretory responses, all of which would be expected to contribute to a significant impact on microbial clearance in the lung.

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    Scientific Reports 03/2014; 4:4466. DOI:10.1038/srep04466 · 5.58 Impact Factor
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    • "As well as the contribution of epithelial cells to CF lung disease, other immune cells that are either resident or recruited appear to contribute to lung defence. Although they lack the characteristic CF lung disease, murine models, in particular, provide evidence of reduced elimination of intracellular P. aeruginosa by macrophages [14], [15] and alterations in macrophage signalling that contribute to elevated inflammatory responses [16]. In line with these observations, we have recently demonstrated that human MDMs from CF patients infected by P. aeruginosa show a significant increase in intracellular bacteria survival compared to non-CF cells [21]. "
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    PLoS ONE 08/2013; 8(8):e71717. DOI:10.1371/journal.pone.0071717 · 3.23 Impact Factor
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    • "CFTR dysfunction results in constitutive, elevated NF-κB activation resulting in increased production of the proinflammatory chemokine, interleukin-8 (Vij et al., 2009; Belcher and Vij, 2010; Bodas and Vij, 2010; Hunter et al., 2010). Moreover, the lack of functional CFTR in macrophages has been reported to increase their responsiveness to inflammatory stimuli via uncontrolled TLR4 signaling (Bruscia et al., 2009, 2011) and to affect their capacity to kill Pseudomonas aeruginosa (Di et al., 2006; Deriy et al., 2009; Zhang et al., 2010; Del Porto et al., 2011). These findings support the role of CFTR dysfunction in favoring bronchopulmonary inflammation. "
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