2. Academic Validation
  3. Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency

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.
Bradley W Richmond 1 2,  Robert M Brucker 3,  Wei Han 1,  Rui-Hong Du 1,  Yongqin Zhang 1,  Dong-Sheng Cheng 1,  Linda Gleaves 1,  Rasul Abdolrasulnia 1,  Dina Polosukhina 4,  Peter E Clark 4,  Seth R Bordenstein 5,  Timothy S Blackwell 1 2 6 7,  Vasiliy V Polosukhin 1
Affiliations

Affiliations

  • 1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
  • 2 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
  • 3 Rowland Institute, Cambridge, Massachusetts 02142, USA.
  • 4 Department of Urologic Surgery, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
  • 5 Departments of Biological Sciences and Pathology, Microbiology, and Immunology, Vanderbilt University, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
  • 6 Department of Cancer Biology, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA.
  • 7 Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212-2637, USA.
PMID: 27046438 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.

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