In this application, we propose to investigate how IL-22 reduces inflammation-induced pulmonary fibrosis by decreasing cxcl9 expression through IL-22 receptor signaling and STAT3 activation in lung epithelial cells. Using a model of hypersensitivity pneumonitis and lung fibrosis caused by repeated exposure to the common environmental microorganism, B. subtilis, we recently reported that IL-22 decreases CXCL9 levels in the lung, Since CXCL9 functions to recruit CXCR3-expressing cells to sites of inflammation, IL-22 reduced accumulation of fibrosis-promoting CXCR3+CD4+ T cells in the lung by down-regulating expression of the CXCR3 ligand, cxcl9. In preliminary experiments, we identified cxcl9 expression in lung epithelial cells. Collectively, this supports our hypothesis tht IL-22 decreases expression of cxcl9 in lung epithelial cells through IL-22 receptor signaling and STAT3 activation resulting in protection against B. subtilis-induced lung inflammation and fibrosis.
In Aim 1, we test the hypothesis that IL-22 down-regulates expression of cxcl9 in type 2 alveolar epithelial cells and Clara cells. If IL-22 does not decrease cxcl9 expression in lung epithelial cells, the application is designed to address not only where cxcl9 is expressed in the lung but also whether cxcl9 is down-regulated in response to treatment with IL-22.
In Aim 2, we test the hypothesis that IL-22 requires STAT3 activation to down-regulate expression of cxcl9 in lung epithelial cells. As a direct extension of Aim1, Aim 2 investigates whether IL-22 receptor signaling through STAT3 activation reduces cxcl9 expression in lung epithelial cells. Again, if type 2 alveolar epithelial cells and/or Clara cells do not require STAT3 activation to decrease cxcl9 expression, the application is designed to answer where STAT3 is activated and whether IL-22 requires STAT3 activation to down-regulate expression of cxcl9. Therefore, completion of the proposed studies will either demonstrate that IL-22 reduces cxcl9 expression through STAT3 activation in lung epithelial cells or will identify which other cells in the lung not only express cxcl9 but also whether IL-22 down-regulates cxcl9 expression through STAT3.
Hypersensitivity pneumonitis (HP) is a lung disease caused by repeated exposure to inhaled particles. Chronic inflammation occurs in the lung of patients who are repeatedly exposed to a wide variety of inhaled particles including bacteria such as Bacillus subtilis. In addition, chronic inflammation can cause scarring of the lungs or """"""""pulmonary fibrosis"""""""". Pulmonary fibrosis occurs in up to 41% of patients with HP resulting in irreversible lun dysfunction with a 5-year mortality of 27% and median survival of 13 years. In a mouse model of HP induced by repeated exposure to the environmental microorganism, Bacillus subtilis, specific cells of the immune system, T cells, express a molecule named IL-22 which suppresses the development of pulmonary fibrosis. The goal of this grant application is to define the mechanism by which IL-22 protects the lung from chronic inflammation and fibrosis caused by repeated exposure to B. subtilis.