SIRT1/FoxO3 axis alteration leads to aberrant immune responses in bronchial epithelial cells.

Serena Di Vincenzo,Dirkje S Postma,Chiara Cipollina,Liboria Siena,Maria Ferraro,Irene H Heijink,Mark Gjomarkaj,Jacobien A Noordhoek,Andreina Bruno,Elisabetta Pace

doi:10.1111/jcmm.13509

Abstract

Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD). The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation. The role of SIRT1/FoxO3 in COPD is largely unknown. This study evaluated whether cigarette smoke, by modulating the SIRT1/FoxO3 axis, affects airway epithelial pro‐inflammatory responses. Human bronchial epithelial cells (16HBE) and primary bronchial epithelial cells (PBECs) from COPD patients and controls were treated with/without cigarette smoke extract (CSE), Sirtinol or FoxO3 siRNA. SIRT1, FoxO3 and NF‐κB nuclear accumulation, SIRT1 deacetylase activity, IL‐8 and CCL20 expression/release and the release of 12 cytokines, neutrophil and lymphocyte chemotaxis were assessed. In PBECs, the constitutive FoxO3 expression was lower in patients with COPD than in controls. Furthermore, CSE reduced FoxO3 expression only in PBECs from controls. In 16HBE, CSE decreased SIRT1 activity and nuclear expression, enhanced NF‐κB binding to the IL‐8 gene promoter thus increasing IL‐8 expression, decreased CCL20 expression, increased the neutrophil chemotaxis and decreased lymphocyte chemotaxis. Similarly, SIRT1 inhibition reduced FoxO3 expression and increased nuclear NF‐κB. FoxO3 siRNA treatment increased IL‐8 and decreased CCL20 expression in 16HBE. In conclusion, CSE impairs the function of SIRT1/FoxO3 axis in bronchial epithelium, dysregulating NF‐κB activity and inducing pro‐inflammatory responses.

Highlights

chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with a multifactorial aetiology
Starting from our previous study in which we demonstrated that cigarette smoke decreases nuclear expression and activity of SIRT1 and forkhead box class O3 (FoxO3) nuclear expression in bronchial epithelial cells [22], in this study, we want to assess the effects of cigarette smoke exposure on the SIRT1/FoxO3 axis and to unravel the key downstream molecular events that contribute to cigarette smoke-induced inflammation and the consequent effects on the immune system
Constitutive protein expression of FoxO3 was significantly lower in primary bronchial epithelial cells (PBECs) from patients with COPD compared to the levels in cells from healthy controls (Fig. 1A)

Summary

Introduction

Cigarette smoke is the major risk factor for the development of COPD [1, 2]. Inhaled cigarette smoke impairs epithelial barrier function [3], induces damage to proteins and organelles via oxidative stress [4] and causes accelerated ageing of the lung [5]. The incidence of COPD increases with age and changes in COPD lungs share features with the ageing phenotype. This supports that COPD is a disease characterized by the combination of ‘inflammation and aging’ (named inflammaging) of the lung [5, 6]. Sirtuin-1 (SIRT1), a NAD+-dependent protein/histone deacetylase, is considered an ‘anti-ageing’ factor. SIRT1 expression is lower in the lung of patients with COPD compared to healthy

Methods

Results

Conclusion