Toll-Like Receptors in Host Defense

There is a growing body of evidence that platelets express Toll-Like Receptors, or TLRs, on their membrane surface. Specifically, numerous groups have identified TLR4 expression on platelets. However, the exact function of this molecule remains unclear. The prevailing view is that the TLR4 ligand, lipopolysaccharide (LPS) is unable to induce P-selectin expression or platelet activation, two hallmark features of platelet activation. However, LPS could induce platelets under flow conditions to bind to fibrinogen and even more avidly to bind adherent neutrophils. The adhesive mechanism does not appear to involve the likely candidates P-selectin or integrin IIbIIIa. Interestingly, during sepsis or models of sepsis both neutrophils and platelets accumulate in the pulmonary and hepatic vasculature and the platelet binding to neutrophils appears to be essential for this recruitment into these organs. The LPS induced neutrophil-platelet interaction leads to supra-activation of the neutrophils leading to profound degranulation but also release of web-like structures consisting of DNA previously termed Neutrophil Extracellular Traps, or NETs. The platelet-neutrophil interactions and ensuing NETs can also be produced using plasma from documented septic patients. The NETs are covered with proteases and other anti-microbial molecules that effectively trap and kill bacteria under flow conditions. However, this comes at the expense of injury to surrounding endothelium. It is our view that NETs are formed in the vasculature through platelets becoming activated by critically high levels of TLR ligands, binding to neutrophils, and, thus, activating the neutrophils to react in a very aggressive manner to try and eradicate bacteria in the blood.