title: Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia.
abstract: Airway epithelial cell responses are critical to the outcome of lung infection. In this study, we aimed to identify unique contributions of epithelial cells during lung infection. To differentiate genes induced selectively in epithelial cells during pneumonia, we compared genome-wide expression profiles from three sorted cell populations: epithelial cells from uninfected mouse lungs, epithelial cells from mouse lungs with pneumococcal pneumonia, and nonepithelial cells from those same infected lungs. Of 1,166 transcripts that were more abundant in epithelial cells from infected lungs compared with nonepithelial cells from the same lungs or from epithelial cells of uninfected lungs, 32 genes were identified as highly expressed secreted products. Especially strong signals included two related secreted and transmembrane (Sectm) 1 genes, Sectm1a and Sectm1b. Refinement of sorting strategies suggested that both Sectm1 products were induced predominantly in conducting airway epithelial cells. Sectm1 was induced during the early stages of pneumococcal pneumonia, and mutation of NF-κB RelA in epithelial cells did not diminish its expression. Instead, type I IFN signaling was necessary and sufficient for Sectm1 induction in lung epithelial cells, mediated by signal transducer and activator of transcription 1. For target cells, Sectm1a bound to myeloid cells preferentially, in particular Ly6G(bright)CD11b(bright) neutrophils in the infected lung. In contrast, Sectm1a did not bind to neutrophils from uninfected lungs. Sectm1a increased expression of the neutrophil-attracting chemokine CXCL2 by neutrophils from the infected lung. We propose that Sectm1a is an epithelial product that sustains a positive feedback loop amplifying neutrophilic inflammation during pneumococcal pneumonia.
authors.affiliation: 1 Pulmonary Center.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kamata
authors.affiliation: 1 Pulmonary Center.|2 Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; and.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: 1 Pulmonary Center.|Departments of 3 Microbiology.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasserman
authors.affiliation: 1 Pulmonary Center.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Zabinski
authors.affiliation: 4 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Constance K
authors.initials: CK
authors.lastname: Yuen
authors.affiliation: 4 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Wing Yi
authors.initials: WY
authors.lastname: Lung
authors.affiliation: 5 Clinical and Translational Science Institute, and.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Gower
authors.affiliation: Departments of 3 Microbiology.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Belkina
authors.affiliation: 1 Pulmonary Center.|6 Medicine.|7 Pathology and Laboratory Medicine, and.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Ramirez
authors.affiliation: 4 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Deng
authors.affiliation: 1 Pulmonary Center.|6 Medicine.|7 Pathology and Laboratory Medicine, and.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Quinton
authors.affiliation: 1 Pulmonary Center.|6 Medicine.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jones
authors.affiliation: 1 Pulmonary Center.|Departments of 3 Microbiology.|6 Medicine.|8 Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D004553:Electric Conductivity; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000502:physiology
chemical_list: D054426:Chemokine CXCL2; D007370:Interferon Type I; D008565:Membrane Proteins; D011994:Recombinant Proteins; C000589185:SECTM1A protein, mouse
keywords: CXCL2; lung epithelium; neutrophil activation; pneumococcal pneumonia; type I IFNs