Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. The major bacterial cause of COPD exacerbations is non-typeable Haemophilus influenzae (NTHi). 25 to over 80% of cases are associated with NTHi. This susceptibility to infection involves a defective production of interleukin (IL)-22 which plays an important role in mucosal defense. Prophylactic administration of flagellin, a Toll-like receptor 5 (TLR5) agonist, protects healthy mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might prevent COPD exacerbations. Mice chronically exposed to cigarette smoke (CS), which presented COPD symptoms, were infected with NTHi and intraperitoneally treated with recombinant flagellin following a prophylactic or therapeutic protocol. Compared with control, cigarette smoke-exposed mice treated with flagellin showed a lower bacterial load in the airways, the lungs and the blood. This protection was associated with an early neutrophilia, a lower production of pro-inflammatory cytokines and an increased IL-22 production. Flagellin treatment decreased the recruitment of inflammatory cells and the lung damages related to exacerbation. Morover, the protective effect of flagellin against NTHi was altered by treatment with anti-IL-22 blocking antibodies in cigarette smoke-exposed mice and in Il22-/- mice. The effect of flagellin treatment did not implicated the anti-bacterial peptides calgranulins and defensin-β2. This study shows that stimulation of innate immunity by a TLR5 ligand is a potent antibacterial treatment in CS-exposed mice, suggesting innovative therapeutic strategies against acute exacerbation in COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and irreversible decline in lung function [1]
We recently reported a defective production of IL-22 in response to bacteria both in COPD patients and mice chronically exposed to cigarette smoke (CS), whereas IL-17 production is only altered after infection by S. pneumoniae [13,14]
The increased susceptibility to infection during COPD is linked to a defect in IL-22 production related with an altered innate immune response [13,22,23]
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and irreversible decline in lung function [1]. The chronic inflammatory response progressively leads to airway remodeling, impaired bacterial clearance and parenchymal destruction in the lungs, further culminating in irreversible airflow limitation [5] as experienced in our murine model of chronic exposure to CS. These components are involved in the increased susceptibility of COPD patients to bacterial and viral airway infections. During COPD, bacterial infection is characterized by an increased influx of immune cells, including neutrophils, macrophages, dendritic cells (DC) and T lymphocytes [3,11,12] This response is not effective enough to clear the pathogens. We showed that the protective effect of flagellin against NTHi is dependent of IL-22 but was not associated with the modulation of calgranulins (S100A8/S100A9) and defensin-β2
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