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.
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. ? ? ?
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