SIGIRR A Negative Regulator of Toll-IL-IR Signaling

描述(申请人提供)：先天免疫系统通过使用Toll样受体(TLRs)家族来感知微生物的入侵，TLRs识别微生物中保守的特定成分，并启动一系列宿主防御机制。TLRs与细胞内Toll-IL-1受体结构域(TIR结构域)中的IL-1受体家族具有同源性。相似的细胞质结构域允许TLRs与IL-1受体共享共同的信号通路，以诱导一系列核心反应，如炎症。然而，单个TLRs也可以诱导针对特定微生物感染的免疫反应。这些免疫反应的失调可能会使宿主容易受到感染，导致致命性全身炎症或慢性炎症，如炎症性肠病。虽然已经投入了巨大的努力来了解这个Toll-IL-1R超家族所使用的机制，但对这些受体的负调控知之甚少。通过数据库检索，我们最近发现了一个新的含有TIR结构域的受体，即单个免疫球蛋白IL-1受体相关分子(SIGIRR)。然而，SIGIRR并不激活这些通路，而是负向调节TLR依赖的反应。通过注射IL-1后趋化因子诱导增强、致命内毒素攻击阈值降低和化学诱导炎症性肠病的易感性增加，SIGIRR缺陷小鼠的炎症反应增强。这些小鼠的细胞对IL-1或某些Toll配体的反应表现出增强的激活。生化分析表明，SIGIRR以配体依赖的方式与Toll-IL-1R信号元件结合。基于这一数据，我们假设SIGIRR作为Toll-IL-LR信号的生物重要调节器发挥作用，从而调节炎症和先天免疫反应。为了验证这一假说，我们将开展以下具体目标：(1)通过体外和体外细胞培养系统阐明SIGIRR在Toll-IL-1受体介导的信号传导中发挥抑制作用的分子机制；(2)通过体内动物模型确定SIGIRR对肠黏膜免疫的影响。通过这些研究，我们将更好地了解SIGIRR对IL-1和Toll配体介导的信号事件的抑制作用，以及SIGIRR的生理功能，这将为我们理解先天免疫反应提供帮助。具体地说，拟议的研究应在天然粘膜免疫领域取得重大进展，并应有助于我们确定SIGIRR作为开发抗炎药物的靶点的潜力。

DESCRIPTION (provided by applicant): The innate immune system senses the invasion of microorganisms by using the family of Toll-like receptors (TLRs), which recognize specific components conserved among microorganisms and initiates a range of host defense mechanisms. The TLRs share sequence homology with the interleukin-1 receptor family in the intracellular Toll-IL-1 receptor domain (TIR domain). Similar cytoplasmic domains allow TLRs to share common signaling pathways with the IL-1 receptor to induce a core set of responses, such as inflammation. However, individual TLRs can also induce immune responses that are specific to a given microbial infection. Dysregulation of these immune responses may leave the host susceptible to infection, lead to lethal systemic inflammation or chronic inflammation such as inflammatory bowel disease. While tremendous effort has been devoted to understanding the mechanisms used by this Toll-IL-1 R superfamily, little is known about the negative regulation of these receptors. Through database searching, we recently discovered a novel TIR-domain containing receptor, the single immunoglobulin IL-1 receptor related molecule (SIGIRR). However, SIGIRR does not activate the pathways and instead negatively modulates TLR-dependent responses. Inflammation is enhanced in SIGIRR-deficient mice, as measured by enhanced chemokine induction after IL-1 injection and a reduced threshold for lethal endotoxin challenge and increased susceptibility for chemically induced inflammatory bowel disease. Cells from these mice show enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicates that SIGIRR binds to the Toll-IL-1 R signaling components in a ligand-dependent manner. Based on this data, we hypothesize that SIGIRR functions as a biologically important modulator of Toll-IL-lR signaling, thereby regulating the inflammatory and innate immune responses. To test this hypothesis, we will carry out the following Specific Aims: (1) Elucidate the molecular mechanism by which SIGIRR exerts its inhibitory role in Toll-IL-1 receptor-mediated signaling using ex vivo and in vitro cell culture systems; (2) Determine the impact of SIGIRR on intestinal mucosal immunity using in vivo animal models. Through these studies, we will have a better understanding about how SIGIRR exerts its inhibitory role on the signaling events mediated by IL-1 and Toll ligands, and also about the physiological function of SIGIRR, which should provide insight into the innate immune responses. Specifically, the proposed studies should result in significant advances in the field of innate mucosal immunity and should also help us to determine the potential of SIGIRR as a target for developing anti-inflammatory drugs.