(508) The lack of IL-17 receptor C limits host resistance and sustains type 17 inflammation during airway chronic infections by Pseudomonas aeruginosa

Background: The exaggerated inflammation and tissue damage, associated to persistent infections, such as Pseudomonas aeruginosa, are central pathological features of Cystic Fibrosis (CF) disease. The interleukin(IL)-17 inflammatory pathway represents an emerging key player in CF pulmonary disease. In this regard, the IL-17 pathway, through IL-17 receptors A (IL-17RA) was already described. Here, we aimed at dissecting the role of IL-17RA mediated by the interaction with other IL-17 receptors (IL-17RC, IL-17RB, IL-17RE) in modulating host resistance against chronic lung infection by P. aeruginosa in murine models.

Methods: C57BL/6N mice were infected with P. aeruginosa CF clinical strain (AA43) embedded in agar beads and the levels of IL-17 cytokines (IL-17A, IL-17F, IL-17E, IL-17B and IL-17C) were evaluated by ELISA. To directly address the contribution of each IL-17Rs (IL-17RC, IL-17RB, IL-17RE), three knockout (KO) mice for each IL-17R were generated by CRISPR/Cas9 technology. Chronic P. aeruginosa infection was established in the Il17rc-/-, Il17rb-/-, Il17re-/- mice and we evaluated bacterial burdens and host defense, such as pro-inflammatory cytokines (ELISA) and lung infiltrating cells (FACS), at the early (2 days) and advanced (28days) phase of chronic infection.

Results: We found that chronic infection by P. aeruginosa was characterised by the presence of neutrophilic inflammation (CD11+, GR-1hi), T cell recruitment and sustained levels of IL-17 cytokines during the early (2-days) and late (28-days) phases of chronic respiratory infection. Moreover, we exploited KO murine models for Il17rc, Il17rb, Il17re genes in order to address the mutual contribution of each IL-17R to the host resistance. Among Il17rc-/-, Il17rb-/-, Il17re-/- mice, only the lack of Il17rc induced higher bacterial burdens in comparison to wt control, after 2 days and after 28 days post challenge. At the advanced stage of chronic infection, we observed a significantly higher incidence of chronic infection in Il17rc-/- mice in comparison to wt control group. After 28 days post challenge, infected il17rc-/- mice showed a significantly elevated neutrophilic recruitment in the airways than wt control mice. Concurrently il17rc-/- mice were characterized by the presence of CD4 T cells secreting IL-17A and high levels of KC, G-CSF and IL6 cytokines in the overall lung.

Conclusions: Our data demonstrated that, among IL-17 receptors, only lack of IL-17RC may contribute to alter host resistance and promote pulmonary type 17 inflammation during CF chronic infection by P. aeruginosa.

Acknowledgements: This work was supported by US Cystic Fibrosis Foundation (LORE20GO)

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