Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency

Nat Commun. 2016 Apr 5;7:11240. doi: 10.1038/ncomms11240.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / immunology*
  • Aging / pathology
  • Airway Remodeling / immunology
  • Aminopyridines / pharmacology*
  • Animals
  • Benzamides / pharmacology*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / immunology
  • Cyclopropanes / pharmacology
  • Disease Models, Animal
  • Gene Expression Regulation
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Innate
  • Immunoglobulin A, Secretory / genetics
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / immunology
  • Lung / drug effects
  • Lung / immunology
  • Lung / microbiology
  • Lung / pathology
  • Matrix Metalloproteinase 12 / genetics
  • Matrix Metalloproteinase 12 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microbiota / immunology*
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / immunology*
  • Pulmonary Disease, Chronic Obstructive / microbiology
  • Pulmonary Emphysema / drug therapy
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / immunology*
  • Pulmonary Emphysema / microbiology
  • Receptors, Polymeric Immunoglobulin / deficiency*
  • Receptors, Polymeric Immunoglobulin / genetics
  • Receptors, Polymeric Immunoglobulin / immunology
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / microbiology
  • Respiratory Mucosa / pathology

Substances

  • Aminopyridines
  • Benzamides
  • Cyclopropanes
  • Immunoglobulin A, Secretory
  • NF-kappa B
  • Phosphodiesterase 4 Inhibitors
  • Receptors, Polymeric Immunoglobulin
  • Roflumilast
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Leukocyte Elastase
  • Matrix Metalloproteinase 12
  • matrix metallopeptidase 12, mouse