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  • br Role of Sponsors br Author Contributions br Conflicts

    2018-10-23


    Role of Sponsors
    Author Contributions
    Conflicts of Interest
    Acknowledgments
    Introduction Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality worldwide. This will be the third cause of deaths worldwide in 2020 according to the WHO. COPD is a lung disorder characterized by progressive and irreversible airflow limitation. Cigarette smoking is a primary risk factor for the development of COPD, although other factors, including pollution and genetic determinants, have been described. Cigarette smoke (CS) chronically triggers inflammatory processes which ultimately alter pulmonary barrier functions and reduce immune defense mechanisms, thus leading to increased susceptibility to respiratory infections (Agusti et al., 2003; Barnes and Stockley, 2005; Fletcher and Peto, 1977; Soler et al., 1999; Soler-Cataluna et al., 2005). Such infections further alter the clinical status of COPD patients thereby indirectly causing extensive morbidity and mortality (Soler et al., 1999). Acute exacerbation of COPD patients is associated with a greater decline in lung function, enhanced oedema as well as airway and systemic inflammation (Agusti et al., 2003). Among major bacterial species causing COPD exacerbation are Streptococcus pneumoniae, non-typeable Haemophilus influenzae and Moraxella catarrhalis (Sethi and Murphy, 2008). Cigarette smoking is associated with diminished antibacterial immune responses and delayed clearance of microbial agents (Drannik et al., 2004). However, it is not well understood how these alterations are controlled during COPD and why COPD patients are more susceptible to infections (Soler-Cataluna et al., 2005). Considering the increasing prevalence of COPD, there is an urgent need to better understand mechanisms leading to exacerbation in COPD patients in order to propose novel therapeutics (Barnes and Stockley, 2005). Among the factors orchestrating the anti-bacterial response, Th17 cytokines, including interleukin (IL)-17 and IL-22, play a major role (Eidenschenk et al., 2014; Ivanov et al., 2013). These cytokines are produced by various dopaminergic of the adaptive and innate immune system. These include conventional T lymphocytes, natural killer (NK) cells, non-conventional T cells (such as γδ T cells, NKT cells and invariant mucosal-associated T (MAIT) cells) and type 3 innate lymphoid cells (ILC3). Production of Th17 cytokines is strongly dependent on IL-1β, IL-23 and IL-6 secretion by antigen presenting cells (APC) (Doisne et al., 2011; Ivanov et al., 2014). Anti-bacterial effects of Th17 cytokines comprise the induction of antimicrobial peptides and neutrophil chemoattractants by airway epithelial cells (Aujla et al., 2008; Wolk et al., 2004). Both IL-17 and IL-22 amplify the granulopoiesis by increasing the expression of G-CSF. In addition, IL-22 plays a central role in the maintenance of the epithelium integrity by limiting cellular apoptosis and by favoring repair/regeneration processes (Sonnenberg et al., 2011). Since Th17 cytokines play major functions in the control of bacterial, including pneumococcal, outgrowth, we hypothesized that their production upon respiratory bacterial challenge could be altered in the context of COPD. Indeed, our data indicate a default in Th17 cytokine production, especially IL-22, in response to S. pneumoniae in a mouse model of COPD induced by chronic CS exposure (Pichavant et al., 2014) and ex vivo in COPD patients. This reduced response was associated with diminished production of Th17 cytokine inducing factors by pulmonary APC. Remarkably, administration of recombinant IL-22 in CS-exposed mice just before the bacterial challenge resulted in accelerated pneumococcal clearance and lowered pulmonary inflammation. Thus, targeting Th17 cytokines might be valuable to limit COPD exacerbation due to bacterial infections.
    Material and Methods
    Results
    Discussion Infection with Sp is one of the main factors responsible for COPD exacerbation (Gaschler et al., 2007; van der Poll and Opal, 2009). In our mouse model mimicking COPD, Sp challenge resulted in greater lung inflammation and tissue remodeling, and therefore an exacerbation of the disease. Combined exposure to CS and SEB resulted in a raised number of lymphocytes and neutrophils, epithelial remodeling and over-production of IL-17 (Huvenne et al., 2011). Gaschler et al. used H. influenza to exacerbate COPD and demonstrated that the bacterial burden observed in COPD mice was mainly due to a skewed inflammatory mediator expression, probably in AM (Gaschler et al., 2009). Innate immunity associated with the recruitment of competent AM and neutrophils is crucial in the early phase of natural anti-pneumococcal host defense and particularly in bacterial clearance (Clement et al., 2008). Such a pattern was observed in our model despite a defective clearance of the pathogen in CS-exposed mice.