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

Richmond BW, Brucker RM, Han W, Du RH, Zhang Y, Cheng DS, Gleaves L, Abdolrasulnia R, Polosukhina D, Clark PE, Bordenstein SR, Blackwell TS, Polosukhin VV
Nat Commun. 2016 7: 11240

PMID: 27046438 · PMCID: PMC4822073 · DOI:10.1038/ncomms11240

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.

MeSH Terms (26)

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

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