Regulation of TLR Signaling and Innate Immunity by RP105

描述（由申请人提供）：toll样受体（TLRs）是一种信号受体，在多种病原体的先天免疫识别中起着核心作用。保守的微生物结构激活TLR信号可促进先天免疫应答的诱导。这种反应必须严格控制。反应中断，延迟，或活力不足可导致感染控制失败。另一方面，过度或不适当的炎症可能是有害的，甚至是致命的——这在先天免疫反应的过度激活中可以看到，这标志着微生物败血症。先天免疫失调被认为是多种A类和B类生物威胁因子引起的疾病发病机制的核心。相反，调节良好的先天免疫反应被认为是宿主对这些病原体成功反应的关键，也是成功接种这些病原体和其他感染因子的关键。通过tlr的信号传导受到严格调控。我们最近发现了一种新的TLR反调控机制- TLR4同源物，RP105。我们发现：(a) RP105的表达与TLR4在抗原提呈细胞上的表达一致；(b) RP105是HEK293细胞中TLR4信号的特异性抑制剂；(2) RP105直接与TLR4相互作用，抑制TLR4信号复合物结合脂多糖（LPS）的能力；(3)在树突状细胞和巨噬细胞中，RP105调控TLR4信号通路；(4) RP105调控体内对LPS的反应；(5)在炎症的微生物和非微生物模型中，RP105都是TLR4信号的重要生物学抑制剂。这些研究的中心假设是，RP105是TLR4信号和TLR4驱动的免疫反应的生理调节剂。这项工作的长期目标是确定对生物威胁剂和其他病原体产生和调节成功免疫反应的分子机制。本研究将在体外和体内研究RP105调节TLR信号和TLR驱动的免疫反应的能力。我们将：(1)明确骨髓细胞中RP105介导的TLR信号调节的分子机制和生物学后果；(2)确定RP105调控B细胞功能的机制；(3)明确RP105在内源性配体响应中调控TLR4信号的作用。

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) are signaling receptors that are central to innate immune recognition of a variety of pathogens. Activation of TLR signaling by conserved microbial structures promotes the induction of innate immune responses. Such responses must be kept under tight control. Responses that are disrupted, delayed, or of insufficient vigor can lead to a failure to control infection. On the other hand, excessive or inappropriate inflammation can be harmful or even fatal- something seen in the hyper-activation of innate immune responses that marks microbial sepsis. Innate immune dysregulation is thought to be central to the pathogenesis of the diseases caused by diverse Category A and B biological threat agents. Conversely, well-regulated innate immune responses are thought to be key to successful host responses to these pathogens, as well as to successful vaccination against these and other infectious agents. Signaling through TLRs is tightly regulated. We recently discovered a novel mechanism of TLR counter- regulation- the TLR4 homolog, RP105. We have found that: (a) RP105 expression mirrors that of TLR4 on antigen presenting cells; (b) RP105 is a specific inhibitor of TLR4 signaling in HEK293 cells; (2) RP105 interacts directly with TLR4, inhibiting the ability of the TLR4 signaling complex to bind lipopolysaccharide (LPS); (3) RP105 regulates TLR4 signaling in dendritic cells and macrophages; (4) RP105 regulates in vivo responses to LPS; and (5) RP105 acts as a biologically important inhibitor of TLR4 signaling in both microbial and non-microbial models of inflammation. The central hypothesis underlying these studies is that RP105 is a physiological regulator of TLR4 signaling and TLR4-driven immune responses. The long-term goal of this work is to define the molecular mechanisms that underlie the generation and regulation of successful immune responses to biological threat agents and other pathogens. The studies in this proposal will characterize, both in vitro and in vivo, the capacity of RP105 to modulate TLR signaling and TLR-driven immune responses. We will: (1) Define the molecular mechanisms and biological consequences of RP105- mediated modulation of TLR signaling in myeloid cells; (2) Determine the mechanisms responsible for modulation of B cell function by RP105; and (3) Define the role of RP105 in regulating TLR4 signaling in response to endogenous ligands.