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Defining the mechanisms by which platelets regulate neutrophil extracellular traps in sepsis (NETsSepsis)
Start date: 23 Jul 2009, End date: 22 Jul 2011 PROJECT  FINISHED 

Despite treatment advances, sepsis kills an estimated 150,000 in the EU annually. Lipopolysaccharide (LPS), neutrophils and platelets all participate in the pathogenesis of severe sepsis, but the inter-relationships between these players are poorly understood. Recently, we demonstrated that activation of neutrophils by platelets is necessary to defend against bacterial infection (Clark et al, Nat Med 2007). In response to endotoxaemia or bacteraemia, neutrophils lodged primarily in lung capillaries and liver sinusoids. Activation of platelets via the LPS receptor, Toll-like Receptor 4 (TLR4), induced platelet binding to adherent neutrophils. This resulted in robust neutrophils activation and the formation of neutrophil extracellular traps (NETs). Plasma from severely septic patients also induced TLR4-dependent platelet binding and production of NETs. These NETs retained their integrity under flow and ensnared bacteria both in vitro and within the liver and lungs. Activation of microbial defence mechanisms also caused tissue injury. We proposed that this novel bacteria trapping mechanism would only occur under extreme conditions such as severe sepsis, and that platelet TLR4 was the threshold switch. Although these studies implicate platelets in the regulation of innate immune function during severe sepsis, it is not yet known how TLR4 activates platelets nor how platelets stimulate neutrophils to release NETs. Experiments will address the hypothesis that platelets regulate the innate immune responses to bacteria through the following specific aims: 1) Investigate TLR4-dependent signalling events in LPS-activated platelets 2)Elucidate the mechanism by which LPS-treated platelets activate neutrophils to trap bacteria in NETs 3)Characterise NET formation in response to septic plasma or other TLR ligands Collectively these experiments will reveal the regulatory pathways governing this novel inflammatory response and, in doing so, will uncover new therapeutic targets
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