SIGIRR A Negative Regulator of Toll-IL-IR Signaling

描述（由申请人提供）：先天免疫系统通过使用Toll样受体（TLR）家族感知微生物的入侵，Toll样受体（TLR）家族识别微生物中保守的特定组分并启动一系列宿主防御机制。TLR在细胞内Toll-IL-1受体结构域（TIR结构域）中与白介素-1受体家族共享序列同源性。类似的胞质结构域允许TLR与IL-1受体共享共同的信号传导途径，以诱导一组核心反应，如炎症。然而，单个TLR也可以诱导特定于给定微生物感染的免疫应答。这些免疫反应的失调可能使宿主易受感染，导致致命的全身性炎症或慢性炎症，如炎症性肠病。虽然已经付出了巨大的努力来理解这个Toll-IL-1 R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TIR结构域的受体，单免疫球蛋白IL-1受体相关分子（SIGIRR）。然而，SIGIRR不激活通路，而是负调节TLR依赖性反应。炎症在SIGIRR缺陷小鼠中增强，如通过IL-1注射后增强的趋化因子诱导和降低的致死内毒素攻击阈值以及增加的对化学诱导的炎性肠病的易感性所测量的。来自这些小鼠的细胞显示响应于IL-1或某些Toll配体的增强的活化。最后，生化分析表明SIGIRR以配体依赖性方式结合Toll-IL-1 R信号传导组分。基于这些数据，我们假设SIGIRR作为Toll-IL-1 R信号传导的生物学重要调节剂发挥作用，从而调节炎症和先天免疫应答。为了验证这一假设，我们将进行以下具体目标：（1）使用离体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其抑制作用的分子机制;（2）使用体内动物模型确定SIGIRR对肠粘膜免疫的影响。通过这些研究，我们将更好地了解SIGIRR如何发挥其对IL-1和Toll配体介导的信号转导事件的抑制作用，以及SIGIRR的生理功能，这将有助于了解先天免疫反应。具体来说，拟议的研究应该导致先天粘膜免疫领域的重大进展，也应该帮助我们确定SIGIRR作为开发抗炎药物靶点的潜力。

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.