Wnt/beta-catenin signaling and innate immunity in pulmonary fibrosis

肺纤维化中的 Wnt/β-连环蛋白信号传导和先天免疫

• 批准号: 9325627
• 负责人: AI P LAM
• 金额: $ 61.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325627
• 关键词: Affect; Alveolar Macrophages; Area; Biological Process; Biology; Bleomycin; Cell physiology; Cells; Choristoma; Data; Development; Disease; Disease Outcome; Disease Progression; Embryo; Etiology; Exhibits; Extracellular Matrix; Felis catus; Fibrosis; Flow Cytometry; Gastrointestinal tract structure; Gene Expression Profiling; Genes; Genetic; Hamman-Rich syndrome; Health; Homeostasis; Host Defense; Immune; Immune response; Injury; Investigation; Lead; Link; Literature; Lung; Mediating; Myeloid Cell Activation; Myeloid Cells; Natural Immunity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Population; Progressive Disease; Pulmonary Fibrosis; Reaction; Recruitment Activity; Research Personnel; Resolution; Role; Severity of illness; Signal Transduction; Skin; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Tissues; beta catenin; cell type; differential expression; genetic signature; improved; indium-bleomycin; insight; lung injury; lung repair; macrophage; monocyte; novel; outcome forecast; prevent; prognostic; receptor; repaired; response; tissue repair

 DESCRIPTION (provided by applicant): Pulmonary fibrosis is the result of dysregulated repair after tissue injury. Idiopathic pulmonary fibrosis (IPF) remains a devastating, progressive disease with no known cure and currently no treatment that effectively alters the disease course. While the inciting etiology of IPF is still not clear, increasing evidence suggests that hot immune responses contribute to the persistent fibrotic reaction and represents a potential new area for therapeutic intervention. The Wnt/β-catenin pathway has been well described as a determiner of cell fate; recent studies showed that canonical Wnt/β-catenin signaling plays a pivotal role in myeloid cell activation in the gastrointestinal tract and skin. Studies from our la demonstrate that global loss of the Wnt co-receptor Lrp5 is protective against bleomycin-induced pulmonary fibrosis and gene expression analysis of Lrp5-null lungs indicates that the pathways most perturbed are related to immune response and extracellular matrix turnover. Consistent with these microarray data, flow cytometry analysis reveals that Wnt/β-catenin signaling is highly activated in lung myeloid cells and that β-catenin/Lrp5 signaling alters macrophage differentiation/activation. Collectively, our data strongly suggest that sustained Wnt signaling is a driver of lung fibrosis and that key Wnt-activated cell types include immune cells. We hypothesize that β-catenin signaling promotes the differentiation of monocytes into recruited alveolar macrophages, which ultimately impacts the innate immune response and aggravates tissue repair. We predict that inhibition of β-catenin signaling in monocyte-derived macrophages promotes the resolution of pulmonary fibrosis (Aim 1). We propose that canonical Wnt/β-catenin is required for differentiation of monocyte-derived alveolar macrophages after lung injury (Aim 2). Thus we anticipate that Wnt/β-catenin dysregulation in a subpopulation of PBMCs can be used to predict disease outcome in patients with IPF (Aim 3). Recruitment of macrophages to the lungs after injury is critical not only for host defense but also tissue repair. This project focuses on a novel and important area of investigation linking a key developmental pathway to the innate immune response in lung repair. The findings from this project will be the first to establish the role of the Wnt/β-catenin pathway in macrophage differentiation/activation in the innate immune response for resolution of lung injury.

 描述（由申请人提供）：肺纤维化是组织损伤后修复失调的结果。特发性肺纤维化（IPF）仍然是一种毁灭性的进行性疾病，没有已知的治愈方法，目前也没有有效改变疾病进程的治疗方法。虽然IPF的诱发病因尚不清楚，但越来越多的证据表明，热免疫应答有助于持续的纤维化反应，并代表了治疗干预的潜在新领域。Wnt/β-连环蛋白通路已被充分描述为细胞命运的决定因素;最近的研究表明，经典Wnt/β-连环蛋白信号传导在胃肠道和皮肤中的骨髓细胞活化中起关键作用。我们的研究表明，Wnt共受体Lrp 5的整体丧失对博来霉素诱导的肺纤维化具有保护作用，并且Lrp 5缺失肺的基因表达分析表明，最受干扰的途径与免疫应答和细胞外基质周转有关。与这些微阵列数据一致，流式细胞术分析揭示了Wnt/β-连环蛋白信号传导在肺骨髓细胞中高度活化，并且β-连环蛋白/Lrp 5信号传导改变巨噬细胞分化/活化。总的来说，我们的数据强烈表明，持续的Wnt信号传导是肺纤维化的驱动因素，关键的Wnt激活细胞类型包括免疫细胞。我们假设β-连环蛋白信号促进单核细胞分化为募集的肺泡巨噬细胞，这最终影响先天免疫应答并促进组织修复。我们预测单核细胞衍生的巨噬细胞中β-连环蛋白信号传导的抑制促进肺纤维化的消退（目的1）。我们提出，典型的Wnt/β-连环蛋白是肺损伤后单核细胞衍生的肺泡巨噬细胞分化所必需的（目的2）。因此，我们预期PBMC亚群中的Wnt/β-连环蛋白失调可用于预测IPF患者的疾病结局（目的3）。损伤后巨噬细胞向肺的募集不仅对于宿主防御而且对于组织修复都是至关重要的。该项目的重点是一个新的和重要的研究领域，将一个关键的发育途径与肺修复中的先天免疫反应联系起来。该项目的发现将首次确定Wnt/β-连环蛋白途径在先天免疫应答中巨噬细胞分化/活化中的作用，以解决肺损伤。