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

 描述(申请人提供)：肺纤维化是组织损伤后失调修复的结果。特发性肺纤维化(IPF)仍然是一种破坏性的进展性疾病，目前还没有已知的治疗方法，也没有有效改变病程的治疗方法。虽然IPF的诱因尚不清楚，但越来越多的证据表明，热免疫反应参与了持续性纤维化反应，并为治疗干预提供了一个潜在的新领域。Wnt/β-catenin通路一直被认为是细胞命运的决定因素；最近的研究表明，经典的Wnt/β-catenin信号通路在胃肠道和皮肤中的髓系细胞激活中起着关键作用。我们实验室的研究表明，Wnt共同受体LRP5的全球缺失对博莱霉素诱导的肺纤维化具有保护作用，LRP5缺失肺的基因表达分析表明，最受干扰的通路与免疫反应和细胞外基质更新有关。与这些微阵列数据一致，流式细胞仪分析显示Wnt/β-catenin信号在肺髓系细胞中高度激活，β-catenin/LRP5信号改变巨噬细胞的分化/激活。总而言之，我们的数据强烈表明，持续的Wnt信号是肺纤维化的驱动因素，关键的Wnt激活的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招募的肺泡巨噬细胞，最终影响先天免疫反应并加重组织修复。我们预测，抑制单核细胞来源的巨噬细胞中的β-连环蛋白信号促进肺纤维化的消退(目标1)。我们认为典型的Wnt/β-catenin对于肺损伤后单核细胞来源的肺泡巨噬细胞的分化是必需的(目标2)。因此，我们预计，外周血单核细胞亚群中的Wnt/β-连环蛋白异常可用于预测特发性肺纤维化患者的疾病结局(目标3)。巨噬细胞在损伤后重新聚集到肺中不仅对宿主防御至关重要，对组织修复也是至关重要的。这个项目集中在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-连环蛋白通路在巨噬细胞分化/激活中的作用，从而解决肺损伤的先天免疫反应。

 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.