title: Roles of lung epithelium in neutrophil recruitment during pneumococcal pneumonia.
abstract: Epithelial cells line the respiratory tract and interface with the external world. Epithelial cells contribute to pulmonary inflammation, but specific epithelial roles have proven difficult to define. To discover unique epithelial activities that influence immunity during infection, we generated mice with nuclear factor-κB RelA mutated throughout all epithelial cells of the lung and coupled this approach with epithelial cell isolation from infected and uninfected lungs for cell-specific analyses of gene induction. The RelA mutant mice appeared normal basally, but in response to pneumococcus in the lungs they were unable to rapidly recruit neutrophils to the air spaces. Epithelial cells expressed multiple neutrophil-stimulating cytokines during pneumonia, all of which depended on RelA. Cytokine expression by nonepithelial cells was unaltered by the epithelial mutation of RelA. Epithelial cells were the predominant sources of CXCL5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas nonepithelial cells were major sources for other neutrophil-activating cytokines. Epithelial RelA mutation decreased whole lung levels of CXCL5 and GM-CSF during pneumococcal pneumonia, whereas lung levels of other neutrophil-recruiting factors were unaffected. Defective neutrophil recruitment in epithelial mutant mice could be rescued by administration of CXCL5 or GM-CSF. These results reveal a specialized immune function for the pulmonary epithelium, the induction of CXCL5 and GM-CSF, to accelerate neutrophil recruitment in the infected lung.
authors.affiliation: 1 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Ayele-Nati N
authors.initials: AN
authors.lastname: Ahyi
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Pepper-Cunningham
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ferrari
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jones
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Quinton
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018375:Neutrophil Activation / Q000276:immunology; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor