Conclusions
Our study demonstrates that platelet TLR9 is a functional platelet receptor that links oxidative stress, innate immunity, and thrombosis.
Objective
To investigate the biological activities of carboxy(alkylpyrrole) protein adducts, an altered-self ligand generated in oxidative stress, on platelet function and thrombosis.
Results
In this study we show that carboxy(alkylpyrrole) protein adducts represent novel unconventional ligands for TLR9. Furthermore, using human and murine platelets, we demonstrate that carboxy(alkylpyrrole) protein adducts promote platelet activation, granule secretion, and aggregation in vitro and thrombosis in vivo via the TLR9/MyD88 pathway. Platelet activation by TLR9 ligands induces IRAK1 and AKT phosphorylation, and it is Src kinase-dependent. Physiological platelet agonists act synergistically with TLR9 ligands by inducing TLR9 expression on the platelet surface. Conclusions: Our study demonstrates that platelet TLR9 is a functional platelet receptor that links oxidative stress, innate immunity, and thrombosis.