Current Concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung Disease

Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. The inflammatory response in CF is dominated by the activation of the innate immune system. Bacteria and fungi represent the key pathogens chronically colonizing the CF airways. In response, innate immune pattern recognition receptors, expressed by airway epithelial and myeloid cells, sense the microbial threat and release chemoattractants to recruit large numbers of neutrophils into CF airways. However, neutrophils fail to efficiently clear the invading pathogens, but instead release harmful proteases and oxidants and finally cause tissue injury. Here, we summarize and discuss current concepts and controversies in the field of innate immunity in CF lung disease, facing the ongoing questions of whether inflammation is good or bad in CF and how innate immune mechanisms could be harnessed therapeutically.

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The chemokine CCL18 characterises Pseudomonas infections in cystic fibrosis lung disease

European Respiratory Journal ◽

10.1183/09031936.00070014 ◽

2014 ◽

Vol 44 (6) ◽

pp. 1608-1615 ◽

Cited By ~ 9

Author(s):

Andreas Hector ◽

Carolin Kröner ◽

Melanie Carevic ◽

Martina Bakele ◽

Nikolaus Rieber ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Gene Expression Analysis ◽

Ex Vivo ◽

Healthy Controls ◽

Protein Levels ◽

Cystic Fibrosis Lung Disease ◽

Potential Biomarker ◽

Infection And Inflammation ◽

Airway Cells

Cystic fibrosis (CF) lung disease is characterised by chronic Pseudomonas aeruginosa infection and leukocyte infiltration. Chemokines recruit leukocytes to sites of infection. Gene expression analysis identified the chemokine CCL18 as upregulated in CF leukocytes. We hypothesised that CCL18 characterises infection and inflammation in patients with CF lung disease.Therefore, we quantified CCL18 protein levels in the serum and airway fluids of CF patients and healthy controls, and studied CCL18 protein production by airway cells ex vivo.These studies demonstrated that CCL18 levels were increased in the serum and airway fluids from CF patients compared with healthy controls. Within CF patients, CCL18 levels were increased in P. aeruginosa-infected CF patients. CCL18 levels in the airways, but not in serum, correlated with severity of pulmonary obstruction in CF. Airway cells isolated from P. aeruginosa-infected CF patients produced significantly higher amounts of CCL18 protein compared with airway cells from CF patients without P. aeruginosa infection or healthy controls.Collectively, these studies show that CCL18 levels characterise chronic P. aeruginosa infection and pulmonary obstruction in patients with CF. CCL18 may, thus, serve as a potential biomarker and therapeutic target in CF lung disease.

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Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease: a review

Journal of Inflammation ◽

10.1186/s12950-017-0176-1 ◽

2017 ◽

Vol 14 (1) ◽

Cited By ~ 33

Author(s):

Sheonagh M. Law ◽

Robert D. Gray

Keyword(s):

Cystic Fibrosis ◽

Immune Response ◽

Lung Disease ◽

Innate Immune Response ◽

Neutrophil Extracellular Traps ◽

Innate Immune ◽

Cystic Fibrosis Lung ◽

Extracellular Traps ◽

Cystic Fibrosis Lung Disease

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Innate immunity in cystic fibrosis lung disease

Journal of Cystic Fibrosis ◽

10.1016/j.jcf.2012.07.003 ◽

2012 ◽

Vol 11 (5) ◽

pp. 363-382 ◽

Cited By ~ 134

Author(s):

D. Hartl ◽

A. Gaggar ◽

E. Bruscia ◽

A. Hector ◽

V. Marcos ◽

...

Keyword(s):

Cystic Fibrosis ◽

Innate Immunity ◽

Lung Disease ◽

Cystic Fibrosis Lung ◽

Cystic Fibrosis Lung Disease

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Update on Calcium Signaling in Cystic Fibrosis Lung Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.581645 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alessandro Rimessi ◽

Veronica A. M. Vitto ◽

Simone Patergnani ◽

Paolo Pinton

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Immune Cells ◽

Cell Function ◽

Autosomal Recessive Disorder ◽

Airway Epithelial ◽

Cystic Fibrosis Lung Disease ◽

Relevant Role ◽

Intracellular Organelles

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator gene, which causes multifunctional defects that preferentially affect the airways. Abnormal viscosity of mucus secretions, persistent pathogen infections, hyperinflammation, and lung tissue damage compose the classical pathological manifestation referred to as CF lung disease. Among the multifunctional defects associated with defective CFTR, increasing evidence supports the relevant role of perturbed calcium (Ca2+) signaling in the pathophysiology of CF lung disease. The Ca2+ ion is a critical player in cell functioning and survival. Its intracellular homeostasis is maintained by a fine balance between channels, transporters, and exchangers, mediating the influx and efflux of the ion across the plasma membrane and the intracellular organelles. An abnormal Ca2+ profile has been observed in CF cells, including airway epithelial and immune cells, with heavy repercussions on cell function, viability, and susceptibility to pathogens, contributing to proinflammatory overstimulation, organelle dysfunction, oxidative stress, and excessive cytokines release in CF lung. This review discusses the role of Ca2+ signaling in CF and how its dysregulation in airway epithelial and immune cells contributes to hyperinflammation in the CF lung. Finally, we provide an outlook on the therapeutic options that target the Ca2+ signaling to treat the CF lung disease.

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