Innate immunity in cystic fibrosis lung disease

Hartl, Dominik; Gaggar, Amit; Bruscia, Emanuela M.; Hector, Andreas; Marcos, Verónica; Jung, Anna; Greene, Catherine M.; McElvaney, Noel G.; Mall, Marcus; Döring, Gerd

doi:10.1016/j.jcf.2012.07.003

Cited by 196 publications

(207 citation statements)

References 270 publications

(334 reference statements)

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“…While the pathogenetic role of CFTR dysfunction in CF lung disease has been studied most extensively in the superficial airway epithelium and submucosal glands, emerging evidence supports the notion that nonepithelial cell types in the lung, such as innate and adaptive immune cells and fibroblasts, also express CFTR [115,116]. Importantly, myeloid cells, i.e.…”

Section: Cftr Dysfunction In Non-epithelial Cellsmentioning

confidence: 99%

“…While our current understanding predicts that CFTR malfunction in airway epithelia is critical for triggering the disease, emerging studies with conditional deletion of CFTR in myeloid cells in mice [120] and studies with morpholino knock-down technology in zebrafish models [121] support the notion that CFTR dysfunction in myeloid cells may contribute to the pathogenesis and outcome of P. aeruginosa infection in CF lung disease. Beyond phagocytes, a potential role of CFTR in innate immunity includes other immune cell types, such as dendritic cells and natural killer T-cells, a topic discussed in more depth previously [115]. Furthermore, recent studies in CF mice and pigs suggest that CFTR malfunction may be implicated in abnormal development of cartilaginous airways that may contribute to early airflow obstruction, air trapping and respiratory dysfunction in CF [122][123][124].…”

Section: Cftr Dysfunction In Non-epithelial Cellsmentioning

confidence: 99%

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CFTR: cystic fibrosis and beyond

2014

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Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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Section: Cftr Dysfunction In Non-epithelial Cellsmentioning

confidence: 99%

Section: Cftr Dysfunction In Non-epithelial Cellsmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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“…Controversies regarding the mechanisms of impaired innate immunity in the CF lung still remain, with several current hypotheses including: airway surface liquid depletion through dysregulation of ENaC, leading to impaired mucociliary clearance (MCC) (8,9); altered Cl 2 concentration in the airway that impairs antibacterial killing (10); and impaired bicarbonate transport into the airway that impairs antibacterial killing (11). Other potential hypotheses of impaired innate immunity in the CF lung include abnormalities in pathogen sensing, leukocyte recruitment, phagocyte function, hyperactivation of immune responses, and mechanisms linking innate and adaptive immunity (12).…”

mentioning

confidence: 99%

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

Sun¹,

Olivier²,

Liang³

et al. 2014

Am J Respir Cell Mol Biol

117

122

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Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets.

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“…P. aeruginosa is well characterized to cause chronic pulmonary infections in cystic fibrosis (CF) patients which lead to inflammation and progressive pulmonary damage, with proinflammatory cytokines, including interleukin1␤ (IL-1␤), elevated in the bronchoalveolar lavage fluid and the sputum (1). IL-1␤ leads to inflammatory cell recruitment and amplification of proinflammatory cytokines that result in bactericidal responses to P. aeruginosa.…”

mentioning

confidence: 99%

Flagellar Motility Is a Key Determinant of the Magnitude of the Inflammasome Response to Pseudomonas aeruginosa

Patankar¹,

Lovewell²,

Poynter

et al. 2013

Infect Immun

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eWe previously demonstrated that bacterial flagellar motility is a fundamental mechanism by which host phagocytes bind and ingest bacteria. Correspondingly, loss of bacterial motility, consistently observed in clinical isolates from chronic Pseudomonas aeruginosa infections, enables bacteria to evade association and ingestion of P. aeruginosa by phagocytes both in vitro and in vivo. Since bacterial interactions with the phagocyte cell surface are required for type three secretion system-dependent NLRC4 inflammasome activation by P. aeruginosa, we hypothesized that reduced bacterial association with phagocytes due to loss of bacterial motility, independent of flagellar expression, will lead to reduced inflammasome activation. Here we report that inflammasome activation is reduced in response to nonmotile P. aeruginosa. Nonmotile P. aeruginosa elicits reduced IL-1␤ production as well as caspase-1 activation by peritoneal macrophages and bone marrow-derived dendritic cells in vitro. Importantly, nonmotile P. aeruginosa also elicits reduced IL-1␤ levels in vivo in comparison to those elicited by wild-type P. aeruginosa. This is the first demonstration that loss of bacterial motility results in reduced inflammasome activation and antibacterial IL-1␤ host response. These results provide a critical insight into how the innate immune system responds to bacterial motility and, correspondingly, how pathogens have evolved mechanisms to evade the innate immune system.

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Innate immunity in cystic fibrosis lung disease

Cited by 196 publications

References 270 publications

CFTR: cystic fibrosis and beyond

CFTR: cystic fibrosis and beyond

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

Flagellar Motility Is a Key Determinant of the Magnitude of the Inflammasome Response to Pseudomonas aeruginosa

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