Boosting the IL-22 response using Flagellin prevents bacterial infection in cigarette smoke-exposed mice.

The progression of chronic obstructive pulmonary disease (COPD), a lung inflammatory disease being the 4(th) cause of death worldwide, is marked by acute exacerbations. These episodes are mostly caused by bacterial infections, frequently due to Streptococcus pneumoniae (Sp). This susceptibility to infection involved a defect in interleukin (IL)-22 which plays a pivotal role in mucosal defense mechanism. Administration of flagellin, a Toll-like receptor 5 (TLR5) agonist can protect mice and primates against respiratory infections in non-pathological background. We hypothesized that TLR5-mediated stimulation of innate immunity might improve the development of bacteria-induced exacerbations in a COPD context. Mice chronically exposed to cigarette smoke (CS), mimicking COPD symptoms, are infected with Sp, and treated in a preventive and a delayed manner with flagellin. Both kind of treatments induced a lower bacterial load in the lungs and blood, and strongly reduced the inflammation and the lung lesions associated with the infection. This protection implicated an enhanced production of IL-22 and involved the recirculation of soluble factors secreted by spleen cells. This is also associated with higher levels of the S100A8 antimicrobial peptide in the lung. Furthermore, human mononuclear cells from not smoker were able to respond to FliC by increasing IL-22 production while active smoker cells do not, a defect associated with an altered IL-23 production. This study shows that stimulation of innate immunity by a TLR5 ligand reduces CS-induced susceptibility to bacterial infection in mice and should be considered in therapeutic strategies against COPD exacerbations.