Control of inflammatory diseases by gp49 receptors

描述(由申请人提供)：对微生物感染的炎症反应是生存的重要组成部分，但过度或长期的炎症反应可能是有害的。我们知识中的一个主要缺口是启动对微生物制剂的先天炎症反应的受体是如何被反调节以防止组织损伤的。Gp49B1受体表达于肥大细胞、巨噬细胞、中性粒细胞和NK细胞表面，在体外和体内都能反向调节适应性免疫系统的激活受体。然而，我们通过建立gp49B1缺失的小鼠发现，该受体也抑制由两种天然反应的介体，即分别来自细菌和基质细胞的脂多糖和干细胞因子所引起的炎症。这一应用的广泛、长期的目标是了解gp49B1如何在体内对抗由先天反应引起的炎症。我们将通过检验一个中心假设来实现这一目标，即gp49B1的表达降低肥大细胞、中性粒细胞和/或巨噬细胞对天然激活刺激的敏感性，从而减少促炎症介质的产生和反应，从而限制体内炎症的病理后果。我们将通过追求以下具体目标来检验这一应用的中心假设。首先，我们将在体内确定gp49B1在调节对内毒素的先天炎症反应和对细菌感染的保护性反应中的作用。其次，我们将确定gp49B1在多大程度上选择性地抑制SCF的肥大细胞激活作用，同时保留其促进生长的作用。成功完成拟议的研究将提供知识，最终将导致更好地理解gp49B1的自然或基于干预的变化如何影响微生物感染的炎症反应过程。gp49B1是人类白细胞免疫球蛋白样受体(LIR)5的小鼠同源物。

DESCRIPTION (provided by applicant): Inflammation in response to microbial infections is an essential component for survival, yet excessive or prolonged inflammatory responses can be detrimental. A major gap in our knowledge is how receptors that initiate innate inflammatory responses to microbial agents are counterregulated to prevent tissue damage. The gp49B1 receptor is expressed on the surface of mast cells, macrophages, neutrophils, and NK cells and counterregulates activating receptors of the adaptive immune system in vitro and in vivo. However, we have found by generating gp49B1 null mice that this receptor also inhibits inflammation induced by two mediators of innate responses, namely, lipopolysaccharide (LPS) and stem cell factor (SCF), derived from bacteria and stromal cells, respectively. The broad, long-term objective of this application is to understand how gp49B1 counterregulates inflammation induced by innate responses in vivo. We will achieve this objective by testing a central hypothesis that expression of gp49B1 decreases the sensitivity of mast cells, neutrophils, and/or macrophages to innate activating stimuli, which reduces the production of and responses to proinflammatory mediators so as to limit pathologic consequences of inflammation in vivo. We will test the central hypothesis of this application by pursing the following Specific Aims. First, we will establish the role of gp49B1 in regulating innate inflammatory responses to LPS and protective responses to bacterial infection in vivo. Second, we will determine the extent to which gp49B1 selectively inhibits the mast cell-activating effects of SCF while preserving its growth-promoting effects. Successful completion of the proposed studies will provide knowledge that will ultimately lead to a better understanding of how natural or intervention-based alterations in gp49B1, which is a mouse homologue of the human leukocyte immunoglobulin-like receptor (LIR) 5, affect the course of inflammatory responses to microbial infections.