Induction of Type I Interferon Signaling by Pseudomonas aeruginosa Is Diminished in Cystic Fibrosis Epithelial Cells
- 1 January 2012
- journal article
- Published by American Thoracic Society in American Journal of Respiratory Cell and Molecular Biology
- Vol. 46 (1), 6-13
- https://doi.org/10.1165/rcmb.2011-0080oc
Abstract
The clinical manifestations of infection in cystic fibrosis (CF) are restricted to the lung, and involve a limited number of pathogens, suggesting a specific defect in mucosal immunity. We postulated that cystic fibrosis transmembrane conductance regulator (CTFR) mutations could affect the activation of type I interferon signaling in airway epithelial cells, which function in immune surveillance and initiate the recruitment and activation of immune cells. In response to infection with Pseudomonas aeruginosa, Ifnb was induced more than 100-fold in the murine lung, and the phosphorylation of STAT1 was similarly induced by the expected TLR4/TRIF/MD2/TBK1 cascade. The stimulation by P. aeruginosa of CF (IB3) cells and control (C-38) human cell lines similarly resulted in the induction of IFN-β, but to a significantly lower extent in CF airway cells. The potential consequences of diminished type I IFN signaling were demonstrated in a murine model of P. aeruginosa pneumonia, pretreatment with polyinosinic:polycytidylic acid significantly enhanced bacterial clearance and correlated with increased numbers of mature CD11c+/CD86+ dendritic cells (DCs) in the lung. Using culture supernatants from CF or control cell lines stimulated with P. aeruginosa, we similarly demonstrated the diminished activation of human monocyte–derived DCs by incubation with CF compared with normal epithelial cell culture supernatants, which was dependent on IFN-β. These observations suggest that dysfunction of the CFTR in airway epithelial cells may contribute to impaired immune surveillance in the CF airway and resultant colonization by P. aeruginosa.Keywords
This publication has 48 references indexed in Scilit:
- TANK-Binding Kinase-1 Plays an Important Role during In Vitro and In Vivo Type I IFN Responses to DNA Virus InfectionsThe Journal of Immunology, 2009
- TLR-Independent Type I Interferon Induction in Response to an Extracellular Bacterial Pathogen via Intracellular Recognition of Its DNACell Host & Microbe, 2008
- Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilizationNature Immunology, 2008
- IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In VivoPLoS Pathogens, 2008
- Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthmaNature Reviews Immunology, 2008
- TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-βNature Immunology, 2008
- The microbial mimic poly IC induces durable and protective CD4+T cell immunity together with a dendritic cell targeted vaccineProceedings of the National Academy of Sciences of the United States of America, 2008
- CXCR3 LIGANDS CONTRIBUTE TO Th1-INDUCED INFLAMMATION BUT NOT TO HOMING OF Th1 CELLS INTO THE LUNGExperimental Lung Research, 2008
- Type I Interferons as Anti-Inflammatory MediatorsScience's STKE, 2007
- Isolation and Generation of Human Dendritic CellsCurrent Protocols in Immunology, 1997