title: CFTR targeting during activation of human neutrophils.
abstract: Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, plays critical roles in phagocytic host defense. However, how activated neutrophils regulate CFTR channel distribution subcellularly is not well defined. To investigate, we tested multiple Abs against different CFTR domains, to examine CFTR expression in human peripheral blood neutrophils by flow cytometry. The data confirmed that resting neutrophils had pronounced CFTR expression. Activation of neutrophils with soluble or particulate agonists did not significantly increase CFTR expression level, but induced CFTR redistribution to cell surface. Such CFTR mobilization correlated with cell-surface recruitment of formyl-peptide receptor during secretory vesicle exocytosis. Intriguingly, neutrophils from patients with ΔF508-CF, despite expression of the mutant CFTR, showed little cell-surface mobilization upon stimulation. Although normal neutrophils effectively targeted CFTR to their phagosomes, ΔF508-CF neutrophils had impairment in that process, resulting in deficient hypochlorous acid production. Taken together, activated neutrophils regulate CFTR distribution by targeting this chloride channel to the subcellular sites of activation, and ΔF508-CF neutrophils fail to achieve such targeting, thus undermining their host defense function.
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Hang Pong
authors.initials: HP
authors.lastname: Ng
authors.affiliation: Department of Medicine, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Valentine
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana; gwang@lsuhsc.edu.|Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana.|Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and.
authors.forename: Guoshun
authors.initials: G
authors.lastname: Wang
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D002462:Cell Membrane / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005089:Exocytosis; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism*; D009895:Opsonin Proteins; D010588:Phagosomes / Q000378:metabolism; D017354:Point Mutation; D000072417:Protein Domains / Q000276:immunology; D021381:Protein Transport; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; C505032:CFTR protein, human; D008070:Lipopolysaccharides; D009895:Opsonin Proteins; D044042:Receptors, Formyl Peptide; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006997:Hypochlorous Acid; D013755:Tetradecanoylphorbol Acetate
keywords: chloride channel; cystic fibrosis; hypochlorous acid oxidant; neutrophil defect; phagocytic host defense