Abstract
Chronic inflammation of the lung, as a consequence of persistent bacterial infections by several opportunistic pathogens represents the main cause of mortality and morbidity in cystic fibrosis (CF) patients. Mechanisms leading to increased susceptibility to bacterial infections in CF are not completely known, although the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in microbicidal functions of macrophages is emerging. Tissue macrophages differentiate in situ from infiltrating monocytes, additionally, mature macrophages from different tissues, although having a number of common activities, exhibit variation in some molecular and cellular functions. In order to highlight possible intrinsic macrophage defects due to CFTR dysfunction, we have focused our attention on in vitro differentiated macrophages from human peripheral blood monocytes. Here we report on the contribution of CFTR in the bactericidal activity against Pseudomonas aeruginosa of monocyte derived human macrophages. At first, by real time PCR, immunofluorescence and patch clamp recordings we demonstrated that CFTR is expressed and is mainly localized to surface plasma membranes of human monocyte derived macrophages (MDM) where it acts as a cAMP-dependent chloride channel. Next, we evaluated the bactericidal activity of P. aeruginosa infected macrophages from healthy donors and CF patients by antibiotic protection assays. Our results demonstrate that control and CF macrophages do not differ in the phagocytic activity when infected with P. aeruginosa. Rather, although a reduction of intracellular live bacteria was detected in both non-CF and CF cells, the percentage of surviving bacteria was significantly higher in CF cells. These findings further support the role of CFTR in the fundamental functions of innate immune cells including eradication of bacterial infections by macrophages.
Highlights
Cystic fibrosis is the most common genetic disorder affecting the Caucasian population
Chronic inflammation of the lung, as a consequence of persistent bacterial infections by several opportunistic pathogens represents the main cause of mortality and morbidity in cystic fibrosis (CF) patients [19]
At present the causes of the inability of CF patients to eradicate bacterial infections have been mainly ascribed to dysfunctions in the defence mechanisms mediated by airway epithelial cells
Summary
Cystic fibrosis is the most common genetic disorder affecting the Caucasian population. The disease is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) which encodes a c-AMP dependent chloride channel [1,2]. Defective chloride secretion due to dysfunctions of CFTR results in the dehydratation of airway liquid leading to depletion of the periciliary layer and production of highly viscoelastic mucus which significantly impact mucociliary clearance and expectoration [3]. This combination of factors prevents the elimination of bacteria from the lung permitting bacterial infections to become established. Besides alteration of the mucociliary clearance system, CFTR mutations might affect other functions of bronchial epithelial cells including the internalization of P. aeruginosa, the release of inflammatory mediators, sphingolipid metabolism and transport of the redox buffer molecule GSH [6,7,8,9]
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