Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway.
Bacterial LPS induces rapid thrombocytopenia, hypotension, and sepsis. Although growing evidence suggests that platelet activation plays a critical role in LPS-induced thrombocytopenia and tissue damage, the mechanism of LPS-mediated platelet activation is unclear. In this study, we show that LPS stimulates platelet secretion of dense and alpha granules as indicated by ATP release and P-selectin expression, and thus enhances platelet activation induced by low concentrations of platelet agonists. Platelets express components of the LPS receptor-signaling complex, including TLR (TLR4), CD14, MD2, and MyD88, and the effect of LPS on platelet activation was abolished by an anti-TLR4-blocking Ab or TLR4 knockout, suggesting that the effect of LPS on platelet aggregation requires the TLR4 pathway. Furthermore, LPS-potentiated thrombin- and collagen-induced platelet aggregation and FeCl(3)-induced thrombus formation were abolished in MyD88 knockout mice. LPS also induced cGMP elevation and the stimulatory effect of LPS on platelet aggregation was abolished by inhibitors of NO synthase and the cGMP-dependent protein kinase (PKG). LPS-induced cGMP elevation was inhibited by an anti-TLR4 Ab or by TLR4 deficiency, suggesting that activation of the cGMP/protein kinase G pathway by LPS involves the TLR4 pathway. Taken together, our data indicate that LPS stimulates platelet secretion and potentiates platelet aggregation through a TLR4/MyD88- and cGMP/PKG-dependent pathway.
Zhang
Guoying
G
Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA.
Han
Jingyan
J
Welch
Emily J
EJ
Ye
Richard D
RD
Voyno-Yasenetskaya
Tatyana A
TA
Malik
Asrar B
AB
Du
Xiaoping
X
Li
Zhenyu
Z
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
C495377:LY96 protein, human; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; D017869:Cyclic GMP-Dependent Protein Kinases; D013917:Thrombin; D006152:Cyclic GMP