Gene environment interaction in COPD: Involvement of a nicotinic receptor gene polymorphism - 17/02/23

Ranked as the third leading cause of death in the world, chronic obstructive pulmonary disease (COPD) remains a major cause of mortality and morbidity in France. Exposure to cigarette smoke (CS), the main risk factor, leads to inflammation and an alteration of the immune response responsible in the long-term for lung structural changes and irreversible alteration of lung function. Nicotine is the cigarette component involved in addiction through interaction with nicotinic receptor (nAChR). Moreover, genetic polymorphism in α5 subunit of nAChR such as rs16969968 (α5SNP) is associated with COPD development [1Hopkins R.J., Duan F., Gamble G.D., Chiles C., Cavadino A., Billings P., et al. Chr15q25 genetic variant (rs16969968) independently confers risk of lung cancer, COPD and smoking intensity in a prospective study of high-risk smokers Thorax 2021 ;  76 : 272-280 [cross-ref]

Cliquez ici pour aller à la section Références] and is more frequent in COPD patients. Expression of α5SNP in mice triggers the development of COPD-like lesions [2Routhier J., Pons S., Freidja M.L., Dalstein V., Cutrona J., Jonquet A., et al. An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions Nat Commun 2021 ;  12 : 6384

Cliquez ici pour aller à la section Références]. We hypothesized that the α5 SNP could directly contribute to COPD development by sensitizing the lung to cigarette smoke (CS) while altering the immune response.

Wild-type C57BL/6 and humanized for α5 SNP were chronically exposed during 1 or 3 months to air or CS to induce COPD development. After sacrifice, bronchoalveolar lavage (BAL) fluids, lungs, spleens and blood samples were collected. Cytokine production, inflammation, cell phenotype and tissue damages were then analyzed.

After 1-month of CS exposure heterozygous α5SNP causes significant lung remodeling mainly in alveolar walls and bronchial epithelium compared to WT mice and homozygous α5SNP. Moreover, Heterozygous α5SNP mice have a higher alteration of respiratory functions than in WT and homozygous mice. Meanwhile both HE and HO α5SNP causes delayed weight gain associated with extensive lung remodeling (emphysema) mainly in alveolar walls and bronchial epithelium after 3 months of CS exposition. The pro-inflammatory cytokines (IL1b, CxCl10, …) are greater in α5SNP compared to WT mice after CS exposure. These modifications were associated with altered respiratory functions and higher recruitment of immune cells (gd T cells, dendritic cells and macrophages) compared to WT mice (Fig. 1).

Expression of α5 SNP seems to sensitize the lung to CS and might facilitate COPD development in mice. These results need to be confirmed in clinic and could pave the way for new therapeutics and biomarkers for COPD.