Regulation of TLR Signaling and Innate Immunity by RP105

描述（由申请人提供）：Toll样受体（TLR）是对多种病原体的先天免疫识别至关重要的信号传导受体。通过保守的微生物结构激活TLR信号传导促进先天免疫应答的诱导。必须严格控制这种反应。反应中断，延迟或活力不足可能导致无法控制感染。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，标志着微生物败血症。先天性免疫失调被认为是由不同的A类和B类生物威胁因子引起的疾病的发病机制的中心。相反，良好调节的先天免疫应答被认为是宿主对这些病原体的成功应答以及针对这些和其他感染因子的成功疫苗接种的关键。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反调节机制--TLR 4同系物RP 105。我们发现：（a）RP 105的表达反映了抗原呈递细胞上TLR 4的表达;（B）RP 105是HEK 293细胞中TLR 4信号传导的特异性抑制剂;（2）RP 105直接与TLR 4相互作用，抑制TLR 4信号传导复合物结合脂多糖（LPS）的能力;（3）RP 105调节树突状细胞和巨噬细胞中TLR 4信号传导;（4）RP 105调节对LPS的体内应答;和（5）RP 105在炎症的微生物和非微生物模型中充当TLR 4信号传导的生物学重要抑制剂。这些研究的核心假设是RP 105是TLR 4信号传导和TLR 4驱动的免疫应答的生理调节剂。这项工作的长期目标是确定产生和调节对生物威胁因子和其他病原体的成功免疫反应的分子机制。本提案中的研究将在体外和体内表征RP 105调节TLR信号传导和TLR驱动的免疫应答的能力。我们将：（1）确定RP 105介导的髓样细胞TLR信号转导调节的分子机制和生物学后果;（2）确定RP 105调节B细胞功能的机制;（3）确定RP 105在响应内源性配体调节TLR 4信号转导中的作用。

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.