TREM2 AND AIRWAY DISEASE

TREM2 和气道疾病

• 批准号: 9335933
• 负责人: Michael J Holtzman
• 金额: $ 44.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335933
• 关键词: Acute; Address; Apoptosis; Apoptotic; Appearance; Cell physiology; Cell surface; Chronic; Chronic Disease; Development; Disease; Double-Stranded RNA; Epithelial Cells; Epithelium; Human; Immune response; In Vitro; Infection; Inflammatory; Inflammatory Response; Interleukin-13; Location; Lung; MAP Kinase Gene; Macrophage Colony-Stimulating Factor; Modeling; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Myelogenous; Nature; Pathway interactions; Peptide Hydrolases; Population; Process; Production; Proteins; Public Health; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Structure of parenchyma of lung; System; TREM2 gene; TYROBP gene; Technology; Tobacco smoking; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Replication; airway epithelium; base; cell type; common treatment; cytokine; effective therapy; experience; feeding; immune function; improved; in vivo; kinase inhibitor; knockout gene; macrophage; mortality; mouse model; pathogen; prevent; receptor; respiratory; respiratory virus; response

Abstract The role of the mucosal immune response in protecting against acute infectious illness versus promoting chronic inflammatory disease must be better defined to understand and treat these conditions. To address this issue, we are pursuing evidence that lung macrophages efficiently infiltrate the airway mucosal epithelium and adjacent parenchyma to control acute respiratory viral infection, but if unchecked could also contribute to chronic airway disease after the infection is cleared. In support of this hypothesis, we have learned that lung macrophages near the airway (in mucosal and adjacent parenchymal locations) express the myeloid receptor TREM-2 as distinct cell-surface and soluble forms, and that each form can stimulate anti-apoptotic signaling in macrophages to allow for macrophage survival. Thus, we showed that cell-surface TREM-2 is increased during viral infection by the action of dsRNA and prevents macrophage apoptosis during acute viral illness, whereas soluble TREM-2 (sTREM-2) is increased after clearance of infection by the actions of IL-13 and DAP12 and prevents macrophage apoptosis to further increase IL-13 production and chronic post-viral disease. The findings suggest that macrophages can be protective during the acute immune response but inflammatory during the chronic immune response to respiratory viral infection based on new actions of the TREM-2 signaling pathway. Preliminary studies of humans show that respiratory viral infection and IL-13 can also increase cell-surface and soluble TREM-2 levels in human macrophages. We now aim to further define the role of macrophage TREM-2 in acute and chronic mucosal immune responses to respiratory viral infection. Critical questions include: how cell-surface and soluble TREM-2 levels are regulated in lung macrophages, and how cell-surface and soluble forms of TREM-2 control anti-apoptotic pathways, especially in macrophage populations near the airway epithelium. We propose that TREM-2 (particularly as the cell-surface form) is an integral component of mucosal immunity whereas an exaggerated level of TREM-2 (particularly as the soluble form) provides a feed-forward mechanism to drive an excessive type 2 immune response. Thus, the cell-surface form of TREM-2 could protect against acute viral infection but the soluble form could promote chronic post-viral disease. We will especially compare the regulation and function of cell-surface to soluble TREM-2 to develop the hypothesis that down-regulating soluble TREM-2 level might even enhance cell-surface TREM-2 level and thereby improve immune function at mucosal barriers. Based on our preliminary studies, we next aim to: (1) define how TREM-2 is expressed, focusing on the appearance of TREM-2 at the cell surface and the cleavage of cell-surface TREM-2 to soluble TREM-2 in macrophages; and (2) define how cell-surface and soluble TREM-2 signal to inhibit apoptosis in macrophages, focusing on any differences between the two forms of TREM-2 in activating downstream signal transduction.

摘要 粘膜免疫应答在预防急性感染性疾病中的作用 必须更好地定义慢性炎症性疾病，以了解和治疗这些疾病。为了解决这个 因此，我们正在寻找肺巨噬细胞有效浸润气道粘膜上皮的证据， 邻近的实质，以控制急性呼吸道病毒感染，但如果不加检查，也可能有助于 感染清除后的慢性气道疾病。为了支持这一假设，我们已经了解到，肺 气道附近的巨噬细胞（在粘膜和邻近的实质位置）表达髓样受体 TREM-2作为不同的细胞表面和可溶形式，并且每种形式都可以刺激细胞凋亡中的抗凋亡信号传导。 以允许巨噬细胞存活。因此，我们发现细胞表面TREM-2在细胞周期中增加。 通过dsRNA的作用抑制病毒感染，并在急性病毒性疾病期间防止巨噬细胞凋亡，而 可溶性TREM-2（斯特雷姆-2）在通过IL-13和DAP 12的作用清除感染后增加， 防止巨噬细胞凋亡，进一步增加IL-13的产生和慢性病毒后疾病。的 研究结果表明，巨噬细胞在急性免疫反应中具有保护作用， 在对呼吸道病毒感染的慢性免疫应答期间，基于TREM-2的新作用， 信号通路对人类的初步研究表明，呼吸道病毒感染和IL-13也可以 增加人巨噬细胞中细胞表面和可溶性TREM-2水平。 我们现在的目标是进一步确定巨噬细胞TREM-2在急性和慢性粘膜免疫中的作用。 对呼吸道病毒感染的反应。关键问题包括：细胞表面和可溶性TREM-2水平 以及TREM-2的细胞表面和可溶性形式如何控制抗凋亡 通路，特别是在气道上皮细胞附近的巨噬细胞群体中。我们建议TREM-2 （特别是作为细胞表面形式）是粘膜免疫的一个组成部分，而夸大的免疫应答是粘膜免疫的一个组成部分。 TREM-2的水平（特别是作为可溶形式）提供了前馈机制，以驱动过量的TREM-2。 2型免疫反应因此，细胞表面形式的TREM-2可以保护免受急性病毒感染， 可溶性形式可促进慢性病毒后疾病。我们将特别比较监管和 细胞表面对可溶性TREM-2的功能，以发展下调可溶性TREM-2 水平甚至可以提高细胞表面TREM-2水平，从而改善粘膜免疫功能 隔栏.基于我们的初步研究，我们接下来的目标是：（1）定义TREM-2是如何表达的，重点是 TREM-2在细胞表面的出现和细胞表面TREM-2裂解成可溶性TREM-2， 巨噬细胞;和（2）定义细胞表面和可溶性TREM-2如何发出信号以抑制巨噬细胞中的细胞凋亡， 集中于两种形式的TREM-2在激活下游信号转导方面的任何差异。