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

Bradley W. Richmond (), Robert M. Brucker, Wei Han, Rui-Hong Du, Yongqin Zhang, Dong-Sheng Cheng, Linda Gleaves, Rasul Abdolrasulnia, Dina Polosukhina, Peter E. Clark, Seth R. Bordenstein, Timothy S. Blackwell and Vasiliy V. Polosukhin
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Bradley W. Richmond: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Robert M. Brucker: Rowland Institute
Wei Han: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Rui-Hong Du: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Yongqin Zhang: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Dong-Sheng Cheng: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Linda Gleaves: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Rasul Abdolrasulnia: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Dina Polosukhina: Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Peter E. Clark: Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Seth R. Bordenstein: Microbiology, and Immunology, Vanderbilt University, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Timothy S. Blackwell: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA
Vasiliy V. Polosukhin: Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, Tennessee 37232-2650, USA

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11240

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