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(申请人提供)：特发性肺纤维化(IPF)是一种以单核细胞炎症和异常胶原沉积为特征的肺泡浸润性疾病。尽管进行了多年的研究，但它仍然是一种终极诊断，影响着全球数百万人。IPF与转化生长因子-1的过度产生和交替激活的(M2)巨噬细胞的出现有关。我们最近发现，抑制M2巨噬细胞分化在博莱霉素吸入或诱导肺组织靶向转化生长因子-1过度表达所致的肺纤维化模型中是改善的。因此，M2的激活是干预肺纤维化的合法靶点。关于转化生长因子-β1在纤维化肺疾病中诱导M2出现和积聚的机制(S)，人们知之甚少。我们最近发现，转化生长因子-1通过信号素7a依赖的途径影响M2表型，该途径涉及整合素亚单位。信号素7a是一种GPI锚定的膜蛋白，我们最近将其与人肺纤维化联系在一起。它通过其两个已知的受体介导免疫事件、轴突引导和肿瘤侵袭，这两个受体是整合素亚单位，它通过神经元引导蛋白Netrin-1和丛状蛋白C1联系在一起。在转化生长因子-1诱导的小鼠肺纤维化模型中进行的初步工作表明，骨髓来源细胞上的Semaphorin 7a表达足以诱导M2激活和纤维化，这些作用是通过整合素亚单位介导的。有趣的是，在这个模型中，纤维化的恢复与Netrin-1表达的显著诱导有关。在一组同步的人类研究中，我们发现IPF患者循环中CD4+淋巴细胞表面Sema 7a的表达以及CD14+单核细胞中整合素和Netrin-1的mRNA表达增强。丛状蛋白C1值不增加。此外，重组Sema 7a刺激正常CD14+单核细胞可诱导一种交替激活的表型，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。这一独特的发现使我们假设，正是CD4+淋巴细胞上的Semaphorin 7a与单核细胞上的1整合素和Netrin-1的相互作用导致了交替的巨噬细胞激活和肺纤维化。该提案的目标1将确定骨髓来源细胞上的Semaphorin 7a促进转化生长因子1暴露的小鼠肺纤维化的关键细胞和机制。AIM 2将探讨在此过程中对Netrin-1的需求。目的3将确定SEMA 7a-β1整合素/Netrin-1轴在IPF患者循环单核细胞交替激活中的作用。目的4将评估CD4+Sema7a+细胞在IPF患者队列中作为生物标记物的能力。