IL-22 Protection in a Murine Model of Hypersensitivity Pneumonitis

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): 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.