MODULATION OF TISSUE INFLAMMATION BY RP105/TLR4

保守的微生物分子特征激活Toll样受体(TLR信号)促进 诱导先天免疫反应和获得性免疫反应。这样的反应需要保持严密 控制力。免疫反应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。高度炎症性 以脓毒症为特征的反应提供了一个范例，更本地化的反应也是如此。 与关节炎相关的不适当的炎症过程。除了发出信号表示存在 除了微生物产物外，TLR途径还参与发出自我改变或受损的信号。 在组织炎症过程中产生的各种分子模式已被证明通过 TLR4，TLRs中最强的信号。 我们最近在髓系细胞中发现了一种新的内源性TLR4信号抑制物：TLR4 同源基因RP105。这些研究背后的中心假设是，RP105起到静音伤害的作用 内源性配体调控TLR4信号通路引起的组织炎症反应 被组织损伤所掩盖。这项研究计划的长期目标是定义分子 器官特异性自身免疫中组织炎症反应调节失调的机制 自身免疫性关节炎等疾病。这项提案中的研究将采用遗传方法 为了确定RP105(和TLR4)在两种明确定义的非微生物产物依赖的小鼠模型中的作用， 局部炎性组织损伤：(1)松节油引起的无菌炎症； (2)抗体诱导的关节炎。

Activation of Toll-like receptor (TLR signaling) by conserved microbial molecular signatures promotes the induction of both innate and adaptive immune responses. Such responses need to be kept under tight control. Immune responses that are 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. The hyperinflammatory responses that characterize sepsis provide a paradigmatic example, as do the more localized inappropriate inflammatory processes associated with arthritis. In addition to signaling the presence of microbial products, the TLR pathway is also involved in signaling the presence of altered or damaged self. A variety of molecular patterns generated during tissue inflammation have been shown to signal through TLR4, the most robustly signaling of the TLRs. We recently discovered a novel endogenous inhibitor of TLR4 signaling in myeloid cells: the TLR4 homolog RP105. The central hypothesis underlying these studies is that RP105 acts to mute injurious tissue inflammatory responses through modulation of TLR4 signaling driven by endogenous ligands unmasked by tissue injury. The long-term goal of this research program is to define the molecular mechanisms that underlie dysregulation of tissue inflammatory responses in organ-specific autoimmune diseases such as the autoimmune arthritides. The studies in this proposal will employ genetic approaches to define the role of RP105 (and TLR4) in two well-defined mouse models of microbial productindependent, localized, inflammatory tissue injury: (1) sterile inflammation induced by oil of turpentine; and (2) antibody-induced arthritis.