CFTR regulates phagosome acidification in macrophages and alters bactericidal activity

Di, Anke; Brown, Mary Elizabeth; Deriy, Ludmila V.; Li, Chunying; Szeto, Frances L.; Chen, Yimei; Huang, Ping; Tong, Jiankun; Naren, Anjaparavanda P.; Bindokas, Vytautas P.; Palfrey, H C; Nelson, Deborah J.

doi:10.1038/ncb1456

Cited by 445 publications

(520 citation statements)

References 49 publications

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“…Various mechanisms have been proposed, such as defective submucosal gland secretion in the airways, abnormal airway surface liquid composition and volume and intrinsic inflammation [29]. In addition, CFTR was found to be involved in phagosomal pH control in alveolar macrophages in one study [30]. Indeed, lysosomes from CFTR-null macrophages displayed acidification defects and were unable to kill internalised bacteria.…”

Section: Discussionmentioning

confidence: 98%

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

Catherinot¹,

Roux²,

Vibet³

et al. 2012

Eur Respir J

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Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused by Mycobacterium abscessus complex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low-dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections.We addressed this issue by means of a case-control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres.No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates.In conclusion, there is no evidence for a link between M. abscessus complex lung disease and inhaled therapies or low-dose azithromycin in patients with CF.

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Section: Discussionmentioning

confidence: 98%

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

Catherinot¹,

Roux²,

Vibet³

et al. 2012

Eur Respir J

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“…Recent studies from our laboratory on freshly isolated epithelial cells from Cftr -deficient mice confirmed previous studies by Di et al . that Cftr controls the pH of at least some vesicle populations in these cells [10]. Further unpublished studies from our group using freshly isolated macrophages from Cftr -deficient mice demonstrate that Cftr controls the pH in a specific vesicle population, most likely secretory lysosomes, already in non-infected cells, while the pH in endocytotic vesicles is independent of Cftr.…”

Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

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“…The dysregulated cytokine secretion of CF epithelial cells plays an important role in creating the inflammatory milieu (3). It has become increasingly clear that the cystic fibrosis transmembrane regulator (CFTR) also plays a role in lung immune cells, and that the dysfunction of the CFTR affects immune cell responses (4)(5)(6)(7)(8)(9)(10)(11). The dysfunction of pulmonary immune cells in CF could result from the lack of their own CFTR function, or may be induced by the altered milieu created by defective CFTR function in epithelial cells (5,8).…”

mentioning

confidence: 99%

“…The dysfunction or lack of CFTR expression in macrophages, neutrophils, and dendritic cells (DCs) results in an inflammatory phenotype (4,5,(8)(9)(10)(11). In addition, antigen presentation is affected in CF.…”

mentioning

confidence: 99%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) leads to chronic inflammation and infection of the respiratory tract. The role of CFTR for cells of the pulmonary immune system is only partly understood. The present study analyzes the phenotype and immune stimulatory capacity of lung dendritic cells (DCs) from CFTR knockout (CF) mice. Total numbers of conventional DCs, plasmacytoid DCs, and CD103-positive DCs were lower in CF mice compared with wild-type (WT) control mice, as was the expression of major histocompatibility complex class II molecules (MHCII), CD40, and CD86. After pulmonary infection with respiratory syncytial virus, DC numbers increased in WT mice but not in CF mice, and the T cellstimulatory capacity of CF DCs was impaired. The culture of CF lung DCs with bronchoalveolar lavage fluid (BALF) from WT mice increased the expression of MHCII, CD40, and CD86. The supplementation of CF BALF with sphingosine-1-phosphate (S1P), a mediator of immune cell migration and activation that is decreased in CF BALF, rescued the reduced expression of MHCII and CD40 in WT lung DCs and human blood DCs. These findings suggest that DCs are impaired in the CF lung, and that altered S1P affects lung DC function. These findings provide a novel link between defective CFTR and pulmonary innate immune dysfunction in CF.

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CFTR regulates phagosome acidification in macrophages and alters bactericidal activity

Cited by 445 publications

References 49 publications

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

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