Platelets express functional Toll-like receptor-4.
Profound thrombocytopenia occurs in humans with sepsis and in mice administered lipopolysaccharide (LPS). Growing evidence indicates that platelets may contribute to these abnormalities, but whether that is a direct result of LPS activation of platelets or an indirect result of other inflammatory mechanisms remains unclear. Here we demonstrate that although platelets do not increase P-selectin expression in response to LPS, platelets bind more avidly to fibrinogen under flow conditions in a Toll-like receptor-4 (TLR4)-dependent manner. In addition, we find that CD41+ megakaryocytes grown from fetal livers and adult circulating platelets express significant amounts of TLR4. LPS induced thrombocytopenia in wild-type mice but not in TLR4-deficient (TLR4def) mice. Wild-type platelets accumulated in the lungs of wild-type mice in response to LPS; TLR4def platelets did not. However, wild-type platelets did not accumulate in the lungs of LPS-treated TLR4def mice. Neutrophils also accumulated in the lungs, and this preceded platelet accumulation. Neutrophil depletion completely abolished LPS-induced platelet sequestration into the lungs, but platelet depletion did not affect neutrophil accumulation. Thus, our data show for the first time that platelets do express functional levels of TLR4, which contribute to thrombocytopenia through neutrophil-dependent pulmonary sequestration in response to LPS.
Andonegui
Graciela
G
Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Kerfoot
Steven M
SM
McNagny
Kelly
K
Ebbert
Kirsten V J
KV
Patel
Kamala D
KD
Kubes
Paul
P
D000818:Animals; D001772:Blood Cell Count; D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion; D005340:Fibrinogen / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007249:Inflammation; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000648:ultrastructure; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009504:Neutrophils / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010973:Platelet Adhesiveness; D010976:Platelet Count; D040201:Platelet Membrane Glycoprotein IIb / Q000096:biosynthesis; D013154:Spleen / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood
D008070:Lipopolysaccharides; D019007:P-Selectin; D040201:Platelet Membrane Glycoprotein IIb; D005340:Fibrinogen; D009195:Peroxidase