The IL-17A/IL-17RA axis during chronic airway infection by Pseudomonas aeruginosa: Implications for host resistance and tolerance.

The pathophysiological mechanisms driving exaggerated inflammation and tissue damage, associated to un-resolved airway infections, in the context of chronic lung diseases remain to be elucidated. In the host-pathogen interplay, two-component defense responses, resistance and tolerance, are increasingly described. Recent reports prompt the hypothesis that chronic lung disease associated to persistent infections, such as Pseudomonas aeruginosa, may be mediated by IL-17 immunity. Thus, we dissected the IL17 pathway during long term chronic infection by P. aerginosa in murine models. When C57Bl/6 mice were infected with P. aeruginosa embedded in agar beads for one month, we found that IL-17A is sustained and secreted by CD4+ T cells at the advanced phases. To directly address the role of IL-17, we infected IL-17a−/−, IL-17ra−/− and congenic controls comparing their host response. Deficiency of IL-17A/IL-17RA axis was associated with: (i) increased incidence of chronic infection and bacterial burden indicating its role in the host resistance to P. aeruginosa; (ii) reduced markers of tissue damage (pro-MMP-9, elastin degradation, TGF-β1), cytokines levels (KC, IL-33) and tissue innate infiltrating cells, proving alteration of host tolerance, through tissue damage control. Blockade of IL-17 activity, by an anti-IL-17A mAb starting from ten days post-infection did not affect host resistance in terms of bacterial load and incidence of infection, but increase mainly host tolerance, reducing exaggerated neutrophils infiltration, and levels of KC, pro-MMP-9, TGF-β1. Overall, the IL-17A cytokine represents a potential host-based intervention to ameliorate lung physiology without compromising host resistance against pathogens during chronic airway infection.