IL-22 Protection in a Murine Model of Hypersensitivity Pneumonitis

描述（由申请人提供）：在本申请中，我们提出研究IL-22如何通过肺上皮细胞中的IL-22受体信号传导和STAT 3活化降低cxcl 9表达来减少炎症诱导的肺纤维化。采用反复暴露于常见环境微生物引起的过敏性肺炎和肺纤维化模型，B。由于CXCL 9的功能是将表达CXCR 3的细胞募集到炎症部位，因此IL-22通过下调CXCR 3配体cxcl 9的表达来减少肺中促进纤维化的CXCR 3 + CD 4 + T细胞的积累。在初步实验中，我们确定了cxcl 9在肺上皮细胞中的表达。总的来说，这支持了我们的假设，即IL-22通过IL-22受体信号传导和STAT 3活化降低肺上皮细胞中cxcl 9的表达，从而导致针对B的保护。枯草杆菌引起的肺部炎症和纤维化。在目的1中，我们检验了IL-22下调2型肺泡上皮细胞和Clara细胞中cxcl 9表达的假设。如果IL-22不降低肺上皮细胞中的cxcl 9表达，则该应用被设计为不仅解决cxcl 9在肺中表达的位置，而且解决cxcl 9是否响应于用IL-22的治疗而下调。在目的2中，我们检验了IL-22需要STAT 3活化以下调肺上皮细胞中cxcl 9的表达的假设。作为Aim 1的直接延伸，Aim 2研究了IL-22受体通过STAT 3活化的信号传导是否降低肺上皮细胞中cxcl 9的表达。同样，如果2型肺泡上皮细胞和/或Clara细胞不需要STAT 3激活来降低cxcl 9表达，则该应用被设计为回答STAT 3在何处被激活以及IL-22是否需要STAT 3激活来下调cxcl 9的表达。因此，所提出的研究的完成将证明IL-22通过肺上皮细胞中的STAT 3活化降低cxcl 9表达，或者将鉴定肺中的哪些其他细胞不仅表达cxcl 9而且鉴定IL-22是否通过STAT 3下调cxcl 9表达。

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.