Boosting the IL‐22 response using flagellin prevents bacterial infection in cigarette smoke‐exposed mice

• Published in: Clinical and experimental immunology Vol. 201; no. 2; pp. 171 - 186
• Main Authors: Koné, B., Pérez‐Cruz, M., Porte, R., Hennegrave, F., Carnoy, C., Gosset, P., Trottein, F., Sirard, J.‐C., Pichavant, M.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2020; John Wiley and Sons Inc
• Subjects: Animals; Bacteria; bacterial infection; Bacterial infections; Calgranulin A - metabolism; Cells, Cultured; Chronic infection; Chronic obstructive pulmonary disease; Cigarette smoke; Cigarette Smoking - adverse effects; Disease Progression; exacerbations; Flagellin; Flagellin - metabolism; Humans; IL‐22; Immunity, Innate; Inflammatory diseases; Innate immunity; Interleukin-22; Interleukin-23 - metabolism; Interleukins - metabolism; Leukocytes (mononuclear); Lung - metabolism; Lung - pathology; Lung diseases; Male; Mice; Mice, Inbred C57BL; Mimicry; Mucosa; Obstructive lung disease; Original; Pneumococcal Infections - immunology; Pulmonary Disease, Chronic Obstructive - immunology; Spleen; Streptococcus infections; Streptococcus pneumoniae; Streptococcus pneumoniae - physiology; Toll-Like Receptor 5 - agonists; Toll-like receptors; Toll‐like receptor 5 agonist; Toll-like receptor 5 agonist; bacterial infection; IL-22; exacerbations; chronic obstructive pulmonary disease
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.13445

Summary The progression of chronic obstructive pulmonary disease (COPD), a lung inflammatory disease being the fourth cause of death worldwide, is marked by acute exacerbations. These episodes are mainly caused by bacterial infections, frequently due to Streptococcus pneumoniae. This susceptibility to infection involves a defect in interleukin (IL)‐22, which plays a pivotal role in mucosal defense mechanism. Administration of flagellin, a Toll‐like receptor 5 (TLR‐5) agonist, can protect mice and primates against respiratory infections in a non‐pathological background. We hypothesized that TLR‐5‐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 S. pneumoniae, and treated in a preventive and a delayed manner with flagellin. Both treatments induced a lower bacterial load in the lungs and blood, and strongly reduced the inflammation and 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 anti‐microbial peptide in the lung. Furthermore, human mononuclear cells from non‐smokers were able to respond to recombinant flagellin 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 TLR‐5 ligand reduces CS‐induced susceptibility to bacterial infection in mice, and should be considered in therapeutic strategies against COPD exacerbations. The progression of COPD is marked by acute exacerbations frequently caused by bacterial infections. Susceptibility to infection during COPD involved a defect in interleukin (IL)‐22. In mice exposed to cigarette smoke, systemic stimulation of the immune system by the TLR5 agonist, flagellin stimulates the immune response both in the spleen and the lung, leading to the production and the circulation of IL‐22. This cytokine participates to activation of airway epithelial cells and increased the secretion of antibacterial peptide. Subsequently, this protects against bacterial expansion and lung tissue alterations in cigarette smoke‐exposed mice.