| First Author | Stark RJ | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 7 | Pages | e41254 |
| PubMed ID | 22911769 | Mgi Jnum | J:189884 |
| Mgi Id | MGI:5447212 | Doi | 10.1371/journal.pone.0041254 |
| Citation | Stark RJ, et al. (2012) Platelet-derived Toll-like receptor 4 (Tlr-4) is sufficient to promote microvascular thrombosis in endotoxemia. PLoS One 7(7):e41254 |
| abstractText | 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-alpha) and interleukin-1 beta (IL-1beta), 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-alpha and IL-1beta. 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-alpha or IL-1beta. 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-alpha or IL-1beta. |
