The nuclear factor kappa-B pathway in airway epithelium regulates neutrophil recruitment and host defence following Pseudomonas aeruginosa infection

Abstract

SummaryPseudomonas aeruginosa pneumonia usually results from a deficit of the innate immune system. To investigate whether inflammatory signalling by airway epithelial cells provides a pivotal line of defence against P. aeruginosa infection, we utilized two separate lines of inducible transgenic mice that express a constitutive activator of the nuclear factor kappa-B (NF-kB) pathway (IKTA) or a dominant inhibitor of NF-kB (DNTA) in airway epithelial cells. Compared with control mice, IKTA mice showed an enhanced host response to P. aeruginosa infection with greater neutrophil influx into the lungs, increased expression of Glu-Leu-Arg-positive (ELR + ) CXC chemokines macrophage inflammatory protein-2 and keratinocyte chemoattractant (KC), superior bacterial clearance and improved survival at 24 h after infection. Neutrophil depletion abrogated the improvement in host defence identified in IKTA mice. In contrast, DNTA mice showed impaired responses to P. aeruginosa infection with higher bacterial colony counts in the lungs, decreased neutrophilic lung inflammation and lower levels of KC in lung lavage fluid. DNTA mice given recombinant KC at the time of P. aeruginosa infection demonstrated improved neutrophil recruitment to the lungs and enhanced bacterial clearance. Our data indicate that the NF-kB pathway in airway epithelial cells plays an essential role in defence against P. aeruginosa through generation of CXC chemokines and recruitment of neutrophils.

Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

“…6a) that is involved in chemotaxis of neutrophils may also be due to higher ROS production in Fus1 Ϫ/Ϫ mice (32)(33)(34). These data introduce the possibility that increased ROS production in Fus1 Ϫ/Ϫ mice contributes to increased NF-B and mTOR pathway activity, which in turn increases neutrophil recruitment (26,27,(35)(36)(37).…”

“…Recognition of bacterial lipopolysaccharides by Toll-like receptors (TLRs) induces airway epithelial NF-B activation, which promotes the production of chemokines involved in neutrophil recruitment and activation (25,26). Through this mechanism, engagement of TLRs regulates host defense following infections caused by Acinetobacter baumannii, Pseudomonas aeruginosa, and Mycoplasma pneumoniae (27)(28)(29). Our analysis of NF-B activation in lung tissues of infected animals showed that at 4 hpi with A. baumannii, NF-B was significantly phosphorylated in Fus1 Ϫ/Ϫ mice, whereas no phosphorylation was observed in WT mice.…”

Neutrophil Recruitment to the Lungs during Bacterial Pneumonia

“…The role of myeloid cells in the production of neutrophil chemokines in response to bacterial lung inflammation is well established (6,35,66). In addition, alveolar endothelial cells are also important for neutrophil recruitment in the lungs in response to LPS challenge (17). Furthermore, recent studies have demonstrated the role of non-bone marrow-derived cells, including respiratory epithelial cells, in regulating neutrophil influx in patients with lung inflammation induced by bacteria and/or their products (18,79).…”

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

“…19,20 To selectively activate IKKb and hence NF-kB in the airway epithelium, hemizygous male mice that contain both transgenes were crossed with homozygous female mice expressing reverse tetracycline transactivator (rtTA) under the control of the CC10 promoter (a gift from Dr. Jeffrey Whitsett). Approximately half of the pups from these matings expressed all three transgenes, thereby enabling the activation of NF-kB in the airway epithelium after treatment with doxycycline (Dox).…”