Novel Immunologic Effects of Semaphorin 7a in IPF

Semaphorin 7a 在 IPF 中的新免疫学作用

• 批准号: 8499413
• 负责人: Erica L Herzog
• 金额: $ 39.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-03 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499413
• 关键词: Affect; Alveolus; Alzheimer' s Disease; Appearance; Biological Markers; Bleomycin; Blood; Blood Circulation; Bone Marrow; Breathing; CD14 gene; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Death; Cells; Chimera organism; Clinical; Collagen; Deposition; Development; Diagnosis; Disease; Event; Fibrosis; Flow Cytometry; Hamman-Rich syndrome; Human; Human Pathology; Immunologics; In Vitro; Infiltration; Inflammation; Integrins; Intervention; Knockout Mice; Link; Lung; Lung diseases; Macrophage Activation; Mediating; Membrane Proteins; Modeling; Mus; Pathway interactions; Patients; Phenotype; Play; Process; Proteins; Pulmonary Fibrosis; Recombinants; Recruitment Activity; Research; Role; Semaphorins; Small Interfering RNA; Surface; Testing; Tissues; Tumor Cell Invasion; Work; axon guidance; clinically significant; cohort; human NTN1 protein; mRNA Expression; macrophage; melanoma; monocyte; mouse model; netrin-1; neuronal guidance; novel; overexpression; plexin; receptor; response; restoration

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a relentless disease characterized by infiltration of the alveolus with monocytic inflammation and abnormal deposits of collagen. Despite many years of research it remains a terminal diagnosis that affects millions of people worldwide. IPF is associated with TGF-¿1 overproduction and the appearance of alternatively activated (M2) macrophages. We have recently shown that inhibition of M2 macrophage differentiation is ameliorative in models of pulmonary fibrosis caused by either bleomycin inhalation or inducible lung targeted TGF-¿1 overexpression. Thus, M2 activation is a legitimate target for intervention in pulmonary fibrosis. Little is known about the mechanism(s) through which TGF-¿1 induces M2 appearance and accumulation in fibrotic lung disease. We have recently found that TGF-¿1 affects M2 phenotypes through a Semaphorin 7a dependent pathway that involves the ¿1-integrin subunit. Semaphorin 7a is a GPI anchored membrane protein that we have recently linked to human lung fibrosis. It mediates immunologic events, axon guidance, and tumor invasion through its two known receptors, the ¿1-integrin subunit, which associates through the neuronal guidance protein Netrin-1, and Plexin C1. Preliminary work performed in a murine model of TGF-¿1 induced lung fibrosis indicates that Semaphorin 7a expression on bone marrow derived cells is sufficient to induce M2 activation and fibrosis and that these effects are mediated via the ¿1-integrin subunit. Interestingly, the restoration of fibrosis in this model is associated with impressive induction of Netrin-1 expression. In a simultaneous set of human studies we have found that surface expression of Sema 7a on CD4+ lymphocytes, and mRNA expression of ¿1 integrin and Netrin-1 in CD14+ monocytes, is enhanced in the circulation of subjects with IPF. Plexin C1 is not increased. In addition, stimulation of normal CD14+ monocytes with recombinant Sema 7a induces an alternatively activated phenotype and ¿1 integrin blockade reduces the CD14+ monocyte to M2 macrophage transition in IPF. The role of Netrin-1 in these processes is not known. This unique constellation of findings leads us to hypothesize that it is the interaction of Semaphorin 7a on CD4+ lymphocytes with the ¿1-integrin and Netrin-1 on monocytes that leads to alternative macrophage activation and pulmonary fibrosis. Aim 1 of this proposal will define the critical cells and mechanisms through which Semaphorin 7a on bone marrow derived cells promotes fibrosis in the TGF-¿1-exposed murine lung. Aim 2 will explore a requirement for Netrin-1 in this process. Aim 3 will determine the role of the Sema 7a-¿1 integrin/Netrin-1 axis in the alternative activation of circulating monocytes obtained from patients with IPF. Aim 4 will assess the ability of CD4+Sema7a+ cells to function as a biomarker in a cohort of patients with IPF.

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种持续性疾病，其特征是单核细胞炎症浸润肺泡和胶原蛋白异常沉积。尽管经过多年的研究，它仍然是影响全世界数百万人的最终诊断。 IPF 与 TGF-¿1 过量产生和替代性激活 (M2) 巨噬细胞的出现有关。我们最近表明，抑制 M2 巨噬细胞分化可以改善由博来霉素吸入或诱导性肺靶向 TGF-¿1 过表达引起的肺纤维化模型。因此，M2 激活是干预肺纤维化的合理目标。关于 TGF-¿1 在纤维化肺病中诱导 M2 出现和积累的机制知之甚少。我们最近发现 TGF-¿1 通过涉及 ¿1-整合素亚基的信号蛋白 7a 依赖性途径影响 M2 表型。 Semaphorin 7a 是一种 GPI 锚定膜蛋白，我们最近发现它与人类肺纤维化有关。它通过其两个已知受体 ¿1-整合素亚基（通过神经元引导蛋白 Netrin-1 和 Plexin C1 结合）介导免疫事件、轴突引导和肿瘤侵袭。在 TGF-β1 诱导的肺纤维化小鼠模型中进行的初步工作表明，骨髓来源细胞上的信号蛋白 7a 表达足以诱导 M2 激活和纤维化，并且这些作用是通过 β1-整合素亚基介导的。有趣的是，该模型中纤维化的恢复与 Netrin-1 表达的显着诱导有关。在一组同时进行的人类研究中，我们发现在 IPF 受试者的循环中，CD4+ 淋巴细胞上的 Sema 7a 表面表达以及 CD14+ 单核细胞中 ¿1 整合素和 Netrin-1 的 mRNA 表达增强。 Plexin C1 不增加。此外，用重组 Sema 7a 刺激正常 CD14+ 单核细胞会诱导替代激活表型，而 ¿1 整合素阻断可减少 IPF 中 CD14+ 单核细胞向 M2 巨噬细胞的转变。 Netrin-1 在这些过程中的作用尚不清楚。这些独特的发现使我们推测，CD4+ 淋巴细胞上的信号蛋白 7a 与单核细胞上的 ¿1-整合素和 Netrin-1 相互作用，导致巨噬细胞活化和肺纤维化。该提案的目标 1 将定义骨髓来源细胞上的 Semaphorin 7a 促进 TGF-¿1 暴露的小鼠肺纤维化的关键细胞和机制。目标 2 将探讨此过程中对 Netrin-1 的需求。目标 3 将确定 Sema 7a-¿1 整合素/Netrin-1 轴在从 IPF 患者获得的循环单核细胞的替代激活中的作用。目标 4 将评估 CD4+Sema7a+ 细胞作为 IPF 患者队列生物标志物的能力。