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

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

doi:10.1038/ncomms11240

Bradley W Richmond, Peter E Clark + Show 11 more

Open Access

https://doi.org/10.1038/ncomms11240

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Journal: Nature communications	Publication Date: Apr 5, 2016
Citations: 82	License type: CC BY 4.0

Affiliation: Vanderbilt University, Rowland Foundation

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.

Highlights

Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood
Our studies indicate that polymeric immunoglobulin receptor (pIgR) À / À mice develop progressive COPD-like airway and parenchymal remodelling as they age, which results from persistent activation of inflammatory signalling by the lung microbiota, pointing to a causative role for secretory immunoglobulin A (SIgA) deficiency in persistent inflammation and disease progression in COPD
These mice appeared healthy at birth and demonstrated no histopathologic changes in the lungs compared with wild-type (WT) littermate controls at 2 months of age, pIgR À / À mice developed COPD-like changes with fibrotic small airway remodelling and emphysematous destruction of the lung parenchyma by 6 months of age, which continued to worsen in

Summary

Introduction

Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. Re-derivation of pIgR À / À 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. The predominant hypothesis regarding COPD pathogenesis has been that inhalation of toxic particles and gases, primarily from cigarette smoke (CS), results in oxidant-mediated injury, airway inflammation and disruption of the protease/anti-protease balance favouring lung parenchymal destruction[5,6,7] This theory does not fully explain the central role of small airways in this disease or continued airway inflammation and disease progression after smoking cessation[8,9]. Our studies indicate that pIgR À / À mice develop progressive COPD-like airway and parenchymal remodelling as they age, which results from persistent activation of inflammatory signalling by the lung microbiota, pointing to a causative role for SIgA deficiency in persistent inflammation and disease progression in COPD

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