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

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.

Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity

“…Accordingly, it was recently reported that expression of a COPD risk allele of CHRNA5 in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylylcyclase activity (Routhier et al, 2021).…”

“…With a wide range of cell types able to produce or sense Ach, non-neuronal Ach serves as a versatile signaling molecule eliciting complex intercellular crosstalk with diverse outcomes; depending on the context, Ach may promote inflammation or conversely exert anti-inflammatory functions (Hollenhorst & Krasteva-Christ, 2021; Kummer & Krasteva-Christ, 2014; Sell et al, 2021). Accordingly, it was recently reported that expression of a COPD risk allele of CHRNA5 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 (Routhier et al, 2021).…”

“…One of the most well-known risk loci is located near the nicotinic acetylcholine receptor CHRNA3/5 genes and has also been associated with increased nicotine dependence and smoking behavior, and lung cancer (Amos et al, 2008;Carlier et al, 2021;Cui et al, 2014;Hobbs et al, 2017;Hung et al, 2008;Pillai et al, 2009;Wilk et al, 2012). Recent work has demonstrated a role for CHRNA5 in the formation of COPD-like lesions in the respiratory epithelium independently of cigarette smoke, suggesting a direct involvement of nAchRs in shaping epithelial integrity (Routhier et al, 2021). The endogenous ligand of nAchR, acetylcholine (Ach), is a classic neurotransmitter synthesized by Choline Acetyltransferase (ChAT) in cholinergic neurons, as well as in immune cells and epithelial cells, such as brush/tuft cells (Kummer & Krasteva-Christ, 2014;Wessler & Kirkpatrick, 2008).…”

Leveraging deep-learning on raw spirograms to improve genetic understanding and risk scoring of COPD despite noisy labels

“…Fifth, though we performed multiple conditional analyses (e.g., included smoking as a covariate and utilized DeepNull to model non-linearity), some detected loci, such as that near CHRNA 2, may be due to an association with smoking. Arguably, such loci remain relevant as smoking is an established cause of COPD, and, as demonstrated at the chromosome 15 locus, smoking-associated loci may have complex effects on phenotypes ([48, 49]). Lastly, our risk prediction model is agnostic to COPD-related phenotypes such as BMI, height, and smoking.…”

Récepteur nicotinique de l’acétylcholine et bronchopneumopathie chronique obstructive

“…Nous avions précédemment décrit l'expression des dif-férentes sous-unités des récepteurs nicotiniques dans le poumon humain [8]. Par des approches complémentaires in vitro, ex vivo, et in vivo chez la souris, nous venons de mettre en évidence le rôle du variant α5SNP dans le développement de lésions pulmonaires similaires à celles observées chez les patients présentant une BPCO [9]. Nous avons d'abord analysé le remodelage épithélial et l'inflammation sur des prélèvements humains de polyposes permettant notamment l'isolement de cellules épithéliales respiratoires.…”