Platelet Derived TLR4 Enhances Microvascular Thrombosis Independent of a Systemic Inflammatory Response

Abstract

Lipopolysacchride (LPS) initiates systemic inflammatory responses and enhances microvascular thrombosis through Toll‐like receptor 4 (TLR‐4). Since platelets express TLR‐4, we examined whether platelet‐derived TLR‐4 was sufficient to mediate LPS‐enhanced thrombosis. We transfused platelets from wild‐type (WT) mice into TLR‐4‐deficient mice and exposed them to either LPS or saline. We then assessed the kinetics of photochemical injury‐induced thrombosis in mouse cremaster venules. LPS enhanced the rates of microvascular thrombosis (times to thrombotic occlusion were reduced by 40–50%) in two strains of TLR‐4‐deficient mice transfused with WT platelets (n=12 per group, p<0.05), but not in control mice transfused with platelets from TLR‐4‐deficient mice (n=12 per group, N.S.). We found no difference in platelet aggregation between WT and TLR‐4‐deficient to account for the results. Further, while LPS increased pro‐inflammatory cytokines by approximately 2 orders of magnitude in wild‐type mice, the responses were absent in TLR4‐deficient mice, despite transfusion of WT platelets. These studies provide evidence that platelet derived TLR‐4 is sufficient to mediate LPS‐enhanced microvascular thrombosis independent of a systemic inflammatory response. Support: T32 HL007939‐07, HL‐079368, and a Merit Review Grant from The Department of Veterans Affairs.