TF Signaling in Systemic Inflammation

描述(由申请人提供)：组织因子(TF)驱动的弥散性血管内凝血是与细菌性败血症和病毒性出血热相关的各种全身炎症反应综合征的特征。在这笔赠款的前一次资助期间，我们使用了严重内毒素血症的小鼠模型来确定凝血酶和蛋白水解酶激活受体(PARs)在调节导致致死性的严重全身炎症中的作用。我们确定淋巴系统是凝血-炎症串扰的意外位置，树突状细胞(DC)既是凝血酶信号转导的目标，也是凝血晚期扩散的来源。我们将促炎症作用分配给凝血酶-PAR1信号，初步数据表明，上游TF-PAR2信号调节全身炎症并提高存活率。在这个相互竞争的延续应用中，我们建议解决这项研究中的新问题，总体目标是进一步定义由DC TF信号控制的调节网络。目的1是确定进行性全身炎症中凝血激活的细胞来源和位置。在这里，我们提出了一个新的概念，即弥漫性血管内凝血是由淋巴系统中激活的树突状细胞启动的。目的2分析转铁蛋白在调节产生白介素10的树突状细胞功能中的作用，并确定转铁蛋白信号控制全身炎症的位置。目标3是表征Tf-PAR2信号下游的保护通路，特别强调白介素6的作用以及Tf信号与调节性T细胞网络的潜在合作。总之，这些实验有望揭示目前尚未完全确定的在炎症和抑制活动之间切换DC的途径，并将促进我们对TF信号如何调节先天免疫反应的理解。公共卫生相关性：阐明这些调节途径将对干扰解除调节的先天免疫反应的新的治疗方法具有广泛的意义。明确TF和凝血信号在炎症反应的放大和控制中的作用，将促进凝血抑制剂和PAR拮抗剂的合理使用，以减轻全身炎症反应综合征。深入了解凝血级联反应的这些调节途径将使治疗方法能够不损害宿主反应的不同阶段的关键保护机制，以应对感染生物体。

DESCRIPTION (provided by applicant): Tissue factor (TF) driven disseminated intravascular coagulation is a hallmark of diverse systemic inflammatory response syndromes associated with bacterial sepsis and viral hemorrhagic fevers. In the previous funding period of this grant, we have used a mouse model of severe endotoxemia to define the roles of coagulation proteases and protease activated receptors (PARs) in regulating severe systemic inflammation leading to lethality. We identified the lymphatic system as the unexpected location for the coagulation-inflammation crosstalk and the dendritic cell (DC) as both the target of coagulation protease signaling and the origin for late stage dissemination of coagulation. We assigned pro-inflammatory roles to thrombin-PAR1 signaling and our preliminary data indicate that upstream TF-PAR2 signaling regulates systemic inflammation and improves survival. In this competing continuation application, we propose to address new questions in this research with the overall goal to further define the regulatory network that is controlled by DC TF signaling. Aim 1 is to define cellular sources and locations of coagulation activation in progressive systemic inflammation. Here we address the novel concept that disseminated intravascular coagulation is initiated by activated DCs in the lymphatic system. Aim 2 is to analyze the role of TF in regulating the function of interleukin 10-producing DCs and to define locations where TF signaling controls systemic inflammation. Aim 3 is to characterize protective pathways downstream of TF-PAR2 signaling with particular emphasis on the role of interleukin 6 and potential collaborations of TF signaling with regulatory T cell networks. Together, these experiments promise to uncover currently incompletely defined pathways that switch DCs between inflammatory and suppressive activity and will advance our understanding of how TF signaling regulates innate immune responses. PUBLIC HEALTH RELEVANCE: Elucidation of these regulatory pathways will have broad implications for new therapeutic approaches to interfere with deregulated innate immune response. Specifically, understanding the role of TF and coagulation signaling in the amplification and control of inflammation will advance the rational use of coagulation inhibitors and PAR antagonists for attenuation of systemic inflammatory response syndromes. In depth knowledge of these regulatory pathways of the coagulation cascade will enable therapeutic approaches that do not impair crucial protective mechanisms in various stages of the host response that copes with infectious organisms.