TF Signaling in Systemic Inflammation

描述（由申请方提供）：组织因子（TF）驱动的弥散性血管内凝血是与细菌性脓毒症和病毒性出血热相关的多种全身炎症反应综合征的标志。在该资助的上一个资助期，我们使用了严重内毒素血症的小鼠模型来确定凝血蛋白酶和蛋白酶激活受体（PAR）在调节导致死亡的严重全身性炎症中的作用。我们确定了淋巴系统作为凝血-炎症串扰的意外位置，树突状细胞（DC）作为凝血蛋白酶信号传导的靶点和凝血晚期播散的起源。我们将促炎作用分配给凝血酶-PAR 1信号传导，我们的初步数据表明，上游TF-PAR 2信号传导调节全身炎症并改善生存。在这个竞争性的继续申请中，我们提出了解决本研究中的新问题，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，我们解决了新的概念，即弥散性血管内凝血是由淋巴系统中激活的树突状细胞。目的2是分析TF在调节产生白细胞介素10的DC功能中的作用，并确定TF信号传导控制全身炎症的位置。目的3是表征TF-PAR 2信号传导下游的保护途径，特别强调白细胞介素6的作用以及TF信号传导与调节性T细胞网络的潜在合作。总之，这些实验有望揭示目前不完全定义的通路，这些通路在炎症和抑制活性之间切换DC，并将促进我们对TF信号传导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新的治疗方法产生广泛的影响，以干扰失调的先天免疫反应。具体而言，了解TF和凝血信号在炎症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，将使治疗方法不会损害在应对感染性生物体的宿主反应的各个阶段中的关键保护机制。

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.