The TLR5 agonist flagellin prevents bacteria-induced chronic obstructive pulmonary disease exacerbations in mice

Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. It is mainly associated to acute exacerbations due to bacterial infection, by non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (SP). Prophylactic administration of flagellin, the Toll-like receptor 5 (TLR5) agonist, protects mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might prevent COPD exacerbation. Flagellin was intraperitoneally administrated to treat NTHi or SP-infected COPD animals. Compared with control, COPD mice treated with flagellin showed a lower bacterial load in the BAL and the lungs and less bacterial dissemination in the blood. This was associated with an early neutrophilia, a lower production of proinflammatory cytokines but also an increased production of anti-bacterial peptides and of IL-22. Interestingly, the treatment with flagellin decreased the inflammatory cell recruitment and limited lung damage related to exacerbation. Lastly, administration of neutralizing anti-IL-22 antibody attenuated the beneficial effect of Flagellin against NTHI infection. This study shows for the first time that innate immunity stimulation with flagellin is a potent antibacterial treatment against exacerbation during experimental COPD through an IL-22 dependent mechanism. This opens the way to innovative therapeutic strategies. This work is sponsored by INSERM-Transfert, Paris, France.