TREM2 AND AIRWAY DISEASE

摘要 粘膜免疫反应在预防急性传染病中的作用与促进作用 必须更好地定义慢性炎症性疾病，以了解和治疗这些疾病。要解决这个问题 ，我们正在寻找证据表明肺巨噬细胞有效地渗透到呼吸道粘膜上皮细胞和 控制急性呼吸道病毒感染的邻近实质，但如果不加以控制，也可能有助于 感染清除后的慢性呼吸道疾病。为了支持这一假设，我们已经了解到肺 靠近呼吸道的巨噬细胞(在粘膜和邻近的实质部位)表达髓系受体。 TREM-2作为不同的细胞表面和可溶性形式，每种形式都可以刺激细胞内的抗凋亡信号。 巨噬细胞允许巨噬细胞存活。因此，我们发现细胞表面的TREM-2在 在急性病毒性疾病期间通过dsRNA的作用进行病毒感染并防止巨噬细胞凋亡，而 在IL-13和DAP12的作用下，感染清除后，可溶性TREM-2(Strem-2)的表达增加 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。这个 研究结果表明，巨噬细胞在急性免疫反应中可以起到保护作用，但会产生炎症反应。 TREM-2在呼吸道病毒感染慢性免疫应答中的新作用 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水平如何 在肺巨噬细胞中被调节，以及细胞表面和可溶性形式的TREM-2如何控制抗凋亡 途径，特别是在靠近呼吸道上皮的巨噬细胞群中。我们建议TREM-2 (尤其是作为细胞表面的形式)是粘膜免疫的一个组成部分，而夸张的 TREM-2的水平(特别是作为可溶性形式)提供了一种前馈机制来驱动过度的 2型免疫反应。因此，细胞表面形式的TREM-2可以预防急性病毒感染，但 可溶性形式可能会促进慢性病毒后疾病。我们将特别比较这一规定和 细胞表面对可溶性TREM-2的作用及下调可溶性TREM-2的假设 甚至可能增加细胞表面TREM-2的水平，从而改善粘膜的免疫功能 障碍。在我们初步研究的基础上，我们接下来的目标是：(1)定义TREM-2的表达方式，重点是 细胞表面TREM-2的出现及细胞表面TREM-2与可溶性TREM-2的裂解 巨噬细胞；以及(2)确定细胞表面和可溶性TREM-2信号如何抑制巨噬细胞的凋亡， 关注两种形式的TREM-2在激活下游信号转导方面的任何差异。

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.