title: Neutrophil-mediated phagocytic host defense defect in myeloid Cftr-inactivated mice.
abstract: Cystic fibrosis (CF) is a common and deadly inherited disease, caused by mutations in the CFTR gene that encodes a cAMP-activated chloride channel. One outstanding manifestation of the disease is the persistent bacterial infection and inflammation in the lung, which claims over 90% of CF mortality. It has been debated whether neutrophil-mediated phagocytic innate immunity has any intrinsic defect that contributes to the host lung defense failure. Here we compared phagosomal CFTR targeting, hypochlorous acid (HOCl) production, and microbial killing of the neutrophils from myeloid Cftr-inactivated (Myeloid-Cftr-/-) mice and the non-inactivated control (Cftrfl10) mice. We found that the mutant CFTR that lacked Exon-10 failed to target to the neutrophil phagosomes. This dysfunction resulted in impaired intraphagosomal HOCl production and neutrophil microbial killing. In vivo lung infection with a lethal dose of Pseudomonas aeruginosa caused significantly higher mortality in the myeloid CF mice than in the controls. The myeloid-Cftr-/- lungs were deficient in bacterial clearance, and had sustained neutrophilic inflammation and stalled transition from early to late immunity. These manifestations recapitulated the symptoms of human CF lungs. The data altogether suggest that myeloid CFTR expression is critical to normal host lung defense. CFTR dysfunction in neutrophils compromises the phagocytic innate immunity, which may predispose CF lungs to infection.
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Hang Pong
authors.initials: HP
authors.lastname: Ng
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Kejing
authors.initials: K
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Hodges
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America; Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Guoshun
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006997:Hypochlorous Acid / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010587:Phagocytosis; D010588:Phagosomes / Q000235:genetics / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology*
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006997:Hypochlorous Acid