The pathophysiological mechanisms driving exaggerated inflammation and tissue damage associated to un-resolved airway infections during chronic lung diseases remain to be elucidated. Recent reports prompt the hypothesis that IL-17 immunity, through IL-17RA mediates host defense and immunopathology during chronic lung disease associated to persistent infections, such as Pseudomonas aeruginosa. Thus, we are dissecting the pleiotropic activities of IL-17RA by the interaction with other IL-17 receptors (IL-17RC, IL-17RB, IL-17RE) during long term chronic infection by P. aeruginosa in murine models and human respiratory samples. When C57Bl/6 mice were challenged with P. aeruginosa embedded in agar beads, we found that IL-17 cytokine family (IL-17A, IL-17F, IL-17E, IL-17B or IL-17C) increased during the early (2 days) and late (28 days) phases of chronic respiratory infection. We are evaluating the dynamic expression of IL-17 receptors by flow cytometry in C57BL/6 mice chronically infected by P. aeruginosa; preliminary data suggest that IL-17 receptors are differently expressed among stromal and immune cells in the lung. To directly address the contribution of each IL-17 receptor during chronic respiratory infections, three new knockout (KO) murine models for IL-17Rs were generated by CRISPR/Cas9 indel-mediated gene KO for each IL-17 receptors (IL-17RC, IL-17RB, IL-17RE). To date, functional validation of the three IL-17 receptors KO murine lines both in vitro and in vivo is in progress. In respiratory samples from Cystic Fibrosis patients, we are evaluating the levels IL-17 cytokine family associated to both early and advanced stages of P. aeruginosa infection, strengthening the importance of IL-17 cytokine family mediated response in the overall progression of chronic airways disease. In conclusion, targeting selectively IL-17s/IL-17Rs axis may provide a novel potential host-based intervention to limit immunopathology during chronic respiratory illnesses, mediated by opportunistic infections.
