Epigenetic regulation of chemokines in lung inflammation

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Neutrophilic inflammation is the dominant lung pathology in cystic fibrosis (CF) which is associated with elevated Interleukin-17 production. Our long-term goal is to elucidate the regulation of IL-17 production and dissect the downstream neutrophilic responses in the lungs. IL-17 promotes the production of CXCR2 ligands including CXCL5, which has chemotactic and activating functions on neutrophil especially during acute inflammatory responses. Preliminary data indicate that IL-17 augments the expression of these chemokines through histone modification. Although IL-17 can promote inflammation through stabilizing mRNAs encoding CXCR2 ligands, the epigenetic regulation described in this proposal is novel and could have significant clinical impact on treatment and diagnosis of chronic inflammatory diseases. We hypothesize that IL-17 enhances CXCR2 ligands production in the epithelium through increasing chromatin accessibility by repressing HDAC5 and that IL-17 induced epithelial CXCL5 is required for chronic neutrophilic inflammation in the lungs. In Aim1, we will determine the roles of epithelial IL-17 receptors in regulating optimal Cxcl5 expression and neutrophil recruitment in chronic inflammation. We will use conditional IL-17R KO mice in established murine models mimicking neutrophilic lung disease in humans. In Aim2, we will determine if the IL-17 induced expression of CXCR2 ligands requires histone deacetylase HDAC5, identified from the preliminary studies. In Aim3, we will seek to inhibit IL-17 mediated lung inflammation in vivo using compounds that disrupt chromatin remodeling and gene expression. The long-term goal of this research will be to maximize the clinical benefit of targeting the IL-17 pathway in chronic inflammation by defining the epigenetic mechanism of IL-17 driven expression of chemokines. This application seeks to shift current research and clinical practice paradigms by identification of a novel epigenetic regulatory mechanism by which IL-17 promotes neutrophilc inflammation in CF epithelium. The findings generated from these aims may have profound translational implications not only to CF but also to other neutrophilic inflammatory conditions.