Platelet-derived Toll-like receptor 4 (Tlr-4) is sufficient to promote microvascular thrombosis in endotoxemia.
Endotoxin (lipopolysaccharide, LPS) produced by gram-negative bacteria initiates a host of pro-inflammatory effects through Toll-like receptor 4 (TLR-4). We reported previously that LPS enhances microvascular thrombosis in cremaster venules of wild-type mice, but had no effect in mice deficient in TLR-4. Since TLR-4 is expressed on various cell types, the cellular origin of TLR-4 responsible for the LPS-enhanced thrombosis remains undetermined. Platelets are known to express functional TLR-4. Platelet-derived TLR-4 has been suggested to mediate various inflammatory responses in endotoxemia, including production of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), two cytokines reported to enhance microvascular thrombosis. We determined whether platelet-derived TLR-4 was sufficient to mediate the enhanced thrombosis induced by endotoxin and whether these responses were accompanied by systemic increases in TNF-α and IL-1β. We isolated platelets from wild-type mice and transfused them into either of two strains of TLR-4-deficient mice (C57BL/10ScN and B6.B10ScN-TLR-4(lps-del)/Jth). The mice were then injected with LPS or saline, and the kinetics of thrombosis were studied 4 hours later. Transfusion of wild-type platelets restored responsiveness to LPS in TLR-4-deficient mice with regards to microvascular thrombosis but not to plasma levels of TNF-α or IL-1β. The accelerated rates of microvascular thrombosis induced by platelet transfusions were specific to TLR-4, since isolation and transfusion of platelets derived from TLR-4-deficient donors did not restore responsiveness to LPS. These studies demonstrate that platelet-derived TLR-4 is sufficient to promote microvascular thrombosis in endotoxemia, independent of systemic increases in TNF-α or IL-1β.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Ryan J
RJ
Stark
Niloufar
N
Aghakasiri
Rolando E
RE
Rumbaut
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology*; D010974:Platelet Aggregation / Q000235:genetics; D013927:Thrombosis / Q000209:etiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4