Activation of neutrophils during bacterial sepsis plays a role both in defense against offending organisms and in tissue damage. In this paper, the investigators demonstrate that the interaction of platelets contributes to the untoward effects of neutrophils in this process. More specifically, the investigators establish a role for TLR 4 on platelets through its interaction with ligands that are released during sepsis. Although others were not able to see expression of activation markers or aggregation as a result of TLR 4 expression on platelets, the investigators here demonstrated that LPS does indeed bind to platelets through TLR 4. LPS-treated platelets are able to bind to adherent neutrophils, and binding is blocked by TLR 4-specific antibodies and specific antagonists to the receptor ligand complexes. Plasma from septic patients induced platelet-neutrophil interactions. This could be recapitulated in a mouse model of endotoxemia where neutrophils localized to post sinusoidal venules and platelets co-localized only when neutrophils were bound. LPS-treated platelets induced neutrophil degranulation and the release of DNA to outside of the cell. This resulted in formation of neutrophil extracellular traps (NETs) that are resistant to shear flow and can trap bacteria under shear flow. The investigators went a step beyond to demonstrate that binding of LPS-activated platelets to neutrophils, but not activated neutrophils alone, caused endothelial cell injury. Organ damage, as measured by a reduction in liver sinusoid perfusion, was induced by platelet:neutrophil complexes and could be reduced by depletion of neutrophils and, less dramatically, platelets from the site.
In Brief
The work here addresses several key components in innate immunity that are responsible for tissue damage during sepsis and include the interaction of platelets with neutrophils and the dependence on the deposition of neutrophils in this process. The investigators show evidence that platelets play a key role in endothelial damage and that this occurs through LPS interaction with platelet TLR 4. This is exciting because the role of TLR 4 expression on platelets was not thought to be an active one since treatment with LPS did not result in upregulation of activation markers or aggregation. It is not platelets alone but rather their TLR 4-induced interaction with neutrophils that appears to be critical in this process. Although phagocytosis remains a central component of neutrophil function during bacterial infection, it appears that, at least in part, TLR 4-dependent platelet binding results in neutrophil degranulation and the release of both DNA and proteolytic enzymes. The combination of neutrophil platelet binding resulted in rapid release of NETs that extend well beyond the neutrophil boundary. Unfortunately, as much as NETs may enhance bacterial trapping, their formation contributes to damage in the liver microcirculation. Further exploration for TLR 4 ligands that may play a role in sepsis may help refine tools to disrupt the platelet neutrophil interaction through TLR 4, a critical and tractable component in this process during bacterial sepsis.
Competing Interests
Dr. Petruzzelli indicated no relevant conflicts of interest.
