An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions

Julie Routhier,Jérôme Cutrona,Muriel Pichavant,Valérian Dormoy,Gwenola Kervoaze,Mark Lathrop,Mohamed Lamine Freidja,Jean-Claude Mérol,Véronique Dalstein,Uwe Maskos,Stéphanie Pons,Jean-Marie Tournier,Antoine Jonquet,Jerry A Stitzel,Nathalie Lalun,Philippe Birembaut,Philippe Gosset

doi:10.1038/s41467-021-26637-6

Abstract

Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target.

Highlights

Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality
We observed an increased proliferation of α5KO and α5SNP basal cells compared to WT (Fig. 5b—control conditions). We demonstrated that this proliferation was reduced in the presence of inhibitors of adenylyl cyclase (AC), protein kinases A and C (PKA/C) or Raf (Fig. 5b), which are key elements of intracellular signaling cascades known to regulate the transcription of genes involved in proliferation[59,60,61], suggesting that these are some of the major pathways implicated (Fig. 5b)
We provide here the first functional link considering the clinical association of α5SNP with Chronic obstructive pulmonary disease (COPD)

Summary

Introduction

Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. We report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. 15q25 encompasses three genes, CHRNA3, CHRNA5, and CHRNB4, coding for the α3, α5, and β4 subunits of the nicotinic acetylcholine receptor (nAChR) This locus has been previously linked to tobacco smoking and nicotine consumption, using GWAS, validated in our transgenic mouse and rat models for increased nicotine intake and relapse[9,10,11], and summarized in our recent review[12]. Simultaneous analysis of modestly (r2 = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42%) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. We reported the expression and the localization of the α5 subunit in airway epithelial cells from bronchi and bronchioles in non-smokers[28]

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Conclusion