IL-22 Protection in a Murine Model of Hypersensitivity Pneumonitis

描述(申请人提供)：在这项申请中，我们建议研究IL-22如何通过IL-22受体信号和肺上皮细胞中STAT3的激活来减少cxcl9的表达，从而减轻炎症诱导的肺纤维化。利用反复暴露于常见环境微生物枯草杆菌引起的过敏性肺炎和肺纤维化模型，我们最近报道了IL-22降低了肺中CXCL9的水平，因为CXCL9具有将表达CXCR3的细胞招募到炎症部位的功能，IL-22通过下调CXCR3配体cxcl9的表达来减少促进纤维化的CXCR3+CD4+T细胞在肺中的积聚。在初步实验中，我们鉴定了cxcl9在肺上皮细胞中的表达。总之，这支持了我们的假设，即IL-22通过IL-22受体信号转导和STAT3激活减少了cxcl9在肺上皮细胞中的表达，从而对枯草杆菌诱导的肺部炎症和纤维化具有保护作用。在目标1中，我们验证了IL-22下调2型肺泡上皮细胞和Clara细胞中cxcl9表达的假设。如果IL-22没有减少肺上皮细胞中cxcl9的表达，该应用程序的设计不仅是为了解决cxcl9在肺中表达的位置，也是为了解决cxcl9是否在IL-22治疗后下调。在目标2中，我们验证了IL-22需要STAT3激活以下调肺上皮细胞中cxcl9表达的假设。作为Aim1的直接延伸，Aim 2研究了通过STAT3激活的IL-22受体信号是否降低了肺上皮细胞中cxcl9的表达。同样，如果2型肺泡上皮细胞和/或Clara细胞不需要激活STAT3来减少cxcl9的表达，该应用程序旨在回答STAT3在哪里激活以及IL-22是否需要STAT3激活来下调cxcl9的表达。因此，这些研究的完成将要么证明IL-22通过激活STAT3减少肺上皮细胞中cxcl9的表达，要么将确定肺中其他哪些细胞不仅表达cxcl9，而且还将确定IL-22是否通过STAT3下调cxcl9的表达。 公共卫生相关性：过敏性肺炎(HP)是一种因反复暴露于可吸入颗粒物而引起的肺部疾病。反复接触各种可吸入颗粒物，包括枯草芽孢杆菌等细菌的患者，肺部会发生慢性炎症。此外，慢性炎症可导致肺部瘢痕形成或“肺纤维化”。高达41%的HP患者会出现肺纤维化，导致不可逆转的肺功能障碍，5年死亡率为27%，中位生存期为13年。在反复暴露于环境微生物导致的幽门螺杆菌小鼠模型中，枯草芽孢杆菌，免疫系统的特定细胞，T细胞，表达一种名为IL-22的分子，它抑制肺纤维化的发展。这项赠款申请的目标是确定IL-22保护肺部免受因反复暴露于枯草杆菌引起的慢性炎症和纤维化的机制。

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. PUBLIC HEALTH RELEVANCE: 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.