Control of inflammatory diseases by gp49 receptors

描述（由申请人提供）：微生物感染引起的炎症是生存的重要组成部分，但过度或延长的炎症反应可能是有害的。我们知识中的一个主要空白是如何启动对微生物试剂的先天炎症反应的受体被反调节以防止组织损伤。gp 49 B1受体在肥大细胞、巨噬细胞、嗜中性粒细胞和NK细胞的表面上表达，并在体外和体内反调节适应性免疫系统的活化受体。然而，我们已经发现，通过产生gp 49 B1基因敲除小鼠，该受体还抑制由两种先天性应答介质诱导的炎症，即分别来源于细菌和基质细胞的脂多糖（LPS）和干细胞因子（SCF）。本申请的广泛的长期目标是了解gp 49 B1如何在体内反调节先天性反应诱导的炎症。我们将通过测试一个中心假设来实现这一目标，即gp 49 B1的表达降低了肥大细胞、中性粒细胞和/或巨噬细胞对先天性激活刺激的敏感性，这减少了促炎介质的产生和对促炎介质的反应，从而限制了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本申请的中心假设。首先，我们将确定gp 49 B1在体内调节对LPS的先天性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gp 49 B1在多大程度上选择性抑制SCF的肥大细胞激活作用，同时保留其促生长作用。成功完成拟议的研究将提供知识，最终将导致更好地了解gp 49 B1（人类白细胞免疫球蛋白样受体（LIR）5的小鼠同源物）的自然或基于干预的改变如何影响微生物感染的炎症反应过程。

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.