Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway

Abstract

While it has been long known that patients with sepsis often have thrombocytopenia and that septic patients with severe thrombocytopenia have a poor prognosis and higher mortality, the role of platelets in the pathogenesis of sepsis is poorly understood. Here we report a protective role of platelets in septic shock. We show that experimental thrombocytopenia by intraperitoneal injection of an anti-glycoprotein Ibα monoclonal antibody increases mortality and aggravates organ failure whereas transfusion of platelets reduces mortality in Lipopolysaccharide-induced endotoxemia and a bacterial infusion mouse sepsis model. Plasma concentrations of proinflammatory cytokines TNF-α and IL-6 are elevated by thrombocytopenia and decreased by platelet transfusion in septic mice. Furthermore, we identify that platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the COX1/PGE2/EP4 dependent pathway. Thus, these findings demonstrate a previously unappreciated role for platelets in septic shock and suggest that platelet transfusion may be effective in treating severe septic patients.

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

“…Previous work has described this type of modulation by platelets in response to LPS. Activated platelets, or activated platelet supernatant, can reduce TNF‐α and IL‐6 production and induce IL‐10 release by both resting21, 28 and LPS‐stimulated human PBMCs19 as well as LPS‐stimulated mouse bone marrow‐derived macrophages 16, 17. Similarly, platelets that have been exposed to high shear stress can induce IL‐10 production in monocyte‐derived immature dendritic cells in response to LPS 29.…”

“…Platelets have been shown to dampen leucocyte activation and pro‐inflammatory cytokine production in both mouse models of sepsis14 and in vitro cell models of infection,15, 16 and this platelet effect is associated with host defence and survival in sepsis 17, 18. The regulatory effect of platelets has largely been characterised in peripheral blood mononuclear cells (PBMCs) in vitro exposed to lipopolysaccharide (LPS; a TLR4 agonist), or in mouse models of sepsis 14, 17, 19, 20. However, the ability of platelets to affect the leucocyte response to a wider range of TLR agonists has not been fully characterised.…”

Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis

“…28,44 Mice that had depleted platelets (supplemental Figure 6A) at the time of infection had increased mortality compared with their IgG-injected controls ( Figure 6A). Of note, the antiplatelet antibody did not affect mortality in noninfected mice ( Figure 6A) or WBC count at time of infection (supplemental Figure 6B).…”

Kruppel-like factor 4 regulates neutrophil activation

“…21,22 To introduce bacterial infection, we injected 20 million E coli (ATCC-25922 strain) into the peritoneal cavity. Animals were monitored for survival curve.…”