Abstract
The platelet glycoprotein (GP) Ib-IX receptor complex is expressed exclusively on the surface of platelets and is well characterized as a primary adhesion receptor supporting normal hemostasis and pathologic thrombosis. Beyond hemostasis and thrombosis, platelets can also participate in the innate immune response and inflammation. While the platelet as a contributor to the immune continuum is recognized, many aspects of the molecular mechanisms whereby platelets influence the immune response are still undefined. Here, we report studies using a murine model of GP Ib-IX deficiency linking GP Ib-IX to the immune response associated with polymicrobial sepsis, as modeled by cecal ligation and puncture (CLP). In the CLP model, genetic absence of the major GP Ib-IX hemostatic ligand, von Willebrand factor (VWF), improves survival following CLP when compared to control wild-type animals (p= 0.003, Logrank analysis). This suggests a VWF role in thrombosis contributes to survival outcome following CLP. In contrast, genetic absence of the VWF platelet receptor, GP Ib-IX, does not improve survival with no statistical difference comparing wild-type animals to GPIb-IX deficient animals. The molecular basis to explain improved survival in VWF-deficient (ligand deficient) but not GPIb-IX deficient (receptor deficient) animals was pursued. We tested the hypothesis GPIb-IX has normal physiologic and pathophysiologic functions beyond platelet adhesion influencing infection and an inflammatory response. Indeed, GPIb-IX influencing the innate immune response is not completely unexpected since a hallmark structural feature of each subunit of the GPIb-IX receptor is leucine rich repeats, the common motif to all members of the toll like receptor family (TLRs). Whether structural similarities are a consequence of ancestral origins for GPIb-IX and TLRs is unknown. We first documented in the absence of murine platelet GP Ib-IX there are reduced platelet-neutrophil and platelet-monocyte interactions under normal conditions and following CLP in whole blood. Whether there are physiologic consequences for disrupting a platelet/monocyte and/or platelet/neutrophil axis was determined via multianalyte profiling of circulating cytokine levels on a Luminex analyzer following CLP. In the absence of GP Ib-IX there is a robust and statistically significant increase 24 hrs following CLP in some of the major proinflammatory cytokines produced by monocytes and macrophages, including TNFα, MCP-1, MIP-β, IL-6, and IL-15. Increases in cytokines, such as IL-5 and IL-13, associated with other immune cells were also observed. These results highlight a coagulation/inflammation interface where the platelet, and specifically GP Ib-IX, contributes to the pathophysiology of CLP. On the one hand, absence of platelet GPIb-IX reduces thrombotic potential, but it occurs at the expense of upregulation of inflammatory cytokine release leading to a reduced survival in CLP. Clearly, survival outcomes in CLP reflect a complex dysregulation of coagulation and inflammation where platelet GPIb-IX likely contributes to both processes with physiologic consequences. Understanding dysregulation of the coagulation/ inflammation interface and identifying a platelet receptor (GPIb-IX) critical to both adds new information to this complex set of pathophysiologic events Sharing the common structural motifs, leucine rich repeats, with the well characterized family of toll-like receptors, platelet GPIb-IX should now be considered an active participant in the inflammatory cascade.
Disclosures:
No relevant conflicts of interest to declare.
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