During the last grant period, our lab has uncovered the stimulation of DEFB4 (previously called 2-defensin 2) or mBD3/4 (mouse equivalent to DEFB4), CCL20, and IL-19 in human and mouse airway epithelial cells by IL- 17A/F. Both DEFB4 or mBD3/4, and CCL20 are known to have anti-microbial activity and they are also the primary ligands for the recruitment of CCR6-expressing cells, such as Th17 and immature dendritic cells, to the airway lumen. Thus, there is an autocrine/paracrine mechanism to regulate the elevation and/or maintenance of IL-17A/F and their producing cells in airway mucosa. Our recent findings demonstrated that IL-17A/F- induced IL-19, a member of IL-10 cytokine family, also stimulates DEFB4 and mBD3/4 expression in vitro. Thus, there is a built-in mechanism in reinforcing the anti-microbial activity and recruitment of Th17 cells to the airway lumen for host defense through IL-17A/F-induced expression of airway epithelial genes. The renewal application will focus on the roles of IL-17A/F-targeted epithelial genes in host defense mechanism. Specifically, we hypothesize that IL-17A/F-induced airway epithelial gene products play very essential roles in bridging the innate and adaptive host defense responses to against bacterial infection in airways. To test this hypothesis, the well-established Klebsiella pneumoniae and the clinically relevant Pseudomonas aeruginosa infection mouse models will be used.
Two Specific Aims are proposed.
Specific aim 1 is to test whether or not IL-17A and/or IL-17F are involved in initiating the production of airway epithelial host innate defense peptides, CCL20 and/or mBD3/4, to combat bacterial infection in infected airways. Specifically, we will carry out a detailed time-course study to establish such a connection between the presence of IL-17 cytokines and the expression of epithelial CCL20 and mBD3/4, and the bacterial clearance in mouse airways after bacterial infection (Aim 1A). This will be followed by the study on genetic null mice to see if IL-17 cytokines and their receptor signaling are required in CCL20 and mBD3/4 induction and subsequent bacterial killing/clearance (Aim 1B).
Aim 1 C is to address if epithelial CCL20 and mBD3/4 induced by IL-17 cytokines are essential for bacterial clearance or not.
For Specific Aim 2, we will focus on the mechanism of IL-17- induced epithelial CCL20 in Th17 cell recruitment to the airways after bacterial infection. Specifically, we will address if there is a time-course correlation on the expression of epithelial CCL20 and Th17 cell recruitment (Aim 2A). This will be followed by the study to demonstrate the function of CCL20 in the recruitment of Th17 cells to the bacterial infected airways (Aim 2B). Using an adoptive transfer approach, we will address if a CCL20/CCR6+ axis is involved in Th17 cell recruitment to the airways (Aim 2C). These studies will illustrate the roles of IL-17-induced epithelial CCL20 and mBD3/4 in initiating both innate and adaptive phases of epithelial host defense to combat bacterial infection in the airways.
Airway epithelial cells are primary targets of bacterial infection. To combat the infection, airway epithelial cells are responsible for the calls of both innate and adaptive host defense mechanisms. The goal of the renewal application is to examine the roles of these innate molecules, CCL20 and mBD3/4, in mouse models after Klebsiella pneumoniae and Pseudomonas aeruginosa infections, using various genetic knockout and transgenic approaches. Such a study will lead to a better understanding of host anti-microbial mechanism that may lead to the development of new therapeutic treatment of bacterial infection in the airways.
|Tsai, Hsing-Chuan; Velichko, Sharlene; Lee, Shanshan et al. (2018) Cholera toxin enhances interleukin-17A production in both CD4+ and CD8+ cells via a cAMP/protein kinase A-mediated interleukin-17A promoter activation. Immunology 154:500-509|
|Tsai, Hsing-Chuan; Wu, Reen (2015) Mechanisms of Cholera Toxin in the Modulation of TH17 Responses. Crit Rev Immunol 35:135-52|
|Statt, Sarah; Ruan, Jhen-Wei; Huang, Chih-Ting et al. (2015) Lipidome and transcriptome profiling of pneumolysin intoxication identifies networks involved in statin-conferred protection of airway epithelial cells. Sci Rep 5:10624|
|Statt, Sarah; Ruan, Jhen-Wei; Hung, Li-Yin et al. (2015) Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells. Am J Respir Cell Mol Biol 53:689-702|
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|Chen, Ching-Hsien; Chiu, Chun-Lung; Adler, Kenneth B et al. (2014) A novel predictor of cancer malignancy: up-regulation of myristoylated alanine-rich C kinase substrate phosphorylation in lung cancer. Am J Respir Crit Care Med 189:1002-4|
|Chen, Ching-Hsien; Statt, Sarah; Chiu, Chun-Lung et al. (2014) Targeting myristoylated alanine-rich C kinase substrate phosphorylation site domain in lung cancer. Mechanisms and therapeutic implications. Am J Respir Crit Care Med 190:1127-38|
|Tsai, Hsing-Chuan; Velichko, Sharlene; Hung, Li-Yin et al. (2013) IL-17A and Th17 cells in lung inflammation: an update on the role of Th17 cell differentiation and IL-17R signaling in host defense against infection. Clin Dev Immunol 2013:267971|
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