title: Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency.
abstract: Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR(-/-)) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR(-/-) mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR(-/-) mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema.
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.|Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Richmond
authors.affiliation: Rowland Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brucker
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Du
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Gleaves
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Rasul
authors.initials: R
authors.lastname: Abdolrasulnia
authors.affiliation: Department of Urologic Surgery, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Polosukhina
authors.affiliation: Department of Urologic Surgery, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
authors.affiliation: Departments of Biological Sciences and Pathology, Microbiology, and Immunology, Vanderbilt University, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Seth R
authors.initials: SR
authors.lastname: Bordenstein
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.|Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.|Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212-2637, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
mesh_terms: D000375:Aging / Q000276:immunology* / Q000473:pathology; D056151:Airway Remodeling / Q000276:immunology; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000276:immunology; D003521:Cyclopropanes / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007071:Immunoglobulin A, Secretory / Q000235:genetics; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D011656:Pulmonary Emphysema / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D019056:Receptors, Polymeric Immunoglobulin / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D007071:Immunoglobulin A, Secretory; D016328:NF-kappa B; D058988:Phosphodiesterase 4 Inhibitors; D019056:Receptors, Polymeric Immunoglobulin; C424423:Roflumilast; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019272:Leukocyte Elastase; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse