Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is associated with chronic inflammation and impaired immune response to pathogens leading to bacteria-induced exacerbation of the disease. A defect in Th17 cytokines in response to Streptococcus pneumoniae, a bacteria associated with COPD exacerbations, has been recently reported. Dendritic cells (DC) are professional antigen presenting cells that drive T-cells differentiation and activation. In this study, we hypothesized that exposure to cigarette smoke, the main risk factor of COPD, might altered the pro-Th17 response to S. pneumoniae in COPD patients and human DC.MethodsPro-Th1 and -Th17 cytokine production by peripheral blood mononuclear cells (PBMC) from COPD patients was analyzed and compared to those from smokers and non-smokers healthy subjects. The effect of cigarette smoke extract (CSE) was analyzed on human monocyte-derived DC (MDDC) from controls exposed or not to S. pneumoniae. Bacteria endocytosis, maturation of MDDC and secretion of cytokines were assessed by flow cytometry and ELISA, respectively. Implication of the oxidative stress was analyzed by addition of antioxidants and mitochondria inhibitors. In parallel, MDDC were cocultured with autologous T-cells to analyze the consequence on Th1 and Th17 cytokine production.ResultsPBMC from COPD patients exhibited defective production of IL-1β, IL-6, IL-12 and IL-23 to S. pneumoniae compared to healthy subjects and smokers. CSE significantly reduced S. pneumoniae-induced MDDC maturation, secretion of pro-Th1 and -Th17 cytokines and activation of Th1 and Th17 T-cell responses. CSE exposure was also associated with sustained CXCL8 secretion, bacteria endocytosis and mitochondrial oxidative stress. Antioxidants did not reverse these effects. Inhibitors of mitochondrial electron transport chain partly reproduced inhibition of S. pneumoniae-induced MDDC maturation but had no effect on cytokine secretion and T cell activation.ConclusionsWe observed a defective pro-Th1 and -Th17 response to bacteria in COPD patients. CSE exposure was associated with an inhibition of DC capacity to activate antigen specific T-cell response, an effect that seems to be not only related to oxidative stress. These results suggest that new therapeutics boosting this response in DC may be helpful to improve treatment of COPD exacerbations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0408-6) contains supplementary material, which is available to authorized users.

Highlights

  • Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation and impaired immune response to pathogens leading to bacteria-induced exacerbation of the disease

  • Since Dendritic cells (DC) play a central role in the host response to bacteria, we evaluated the effects of cigarette smoke extract (CSE) on their capacity to initiate a Th17 response against S. pneumoniae, on bacteria uptake and on costimulatory molecule expression and cytokine secretion

  • CXCL8 production by peripheral blood mononuclear cells (PBMC) from COPD patients activated by S. pneumoniae was unchanged the CXCL8 levels were similar in the 3 groups (Additional file 2)

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Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation and impaired immune response to pathogens leading to bacteria-induced exacerbation of the disease. Oxidative stress induced by cigarette smoke induces a chronic lung inflammation responsible for a non-reversible airflow limitation and an impaired immune lung defenses leading to airway bacterial infections [2, 3]. Most of these are due to Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis [4]. These infectious episodes are the major cause of acute exacerbations which have a strong impact on mortality and on disease-related costs [5]. Studies reported that the mucosal inflammation is increased during COPD disease, recent evidences demonstrated that the immune response to micro-organisms is altered [7]

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