Engagement of Platelet Toll-Like Receptor 9 by Novel Endogenous Ligands Promotes Platelet Hyper-Reactivity and Thrombosis
Rationale: A prothrombotic state and increased platelet reactivity are common in pathophysiological conditions associated with oxidative stress and infections. Such conditions are associated with an appearance of altered-self ligands in circulation that can be recognized by Toll-like receptors (TLR). Platelets express a number of TLR, including TLR9, however, the role of TLR in platelet function and thrombosis is poorly understood.
Objective: To investigate the biological activities of carboxy(alkylpyrrole) protein adducts (CAPs), an altered self-ligand generated in oxidative stress, on platelet function and thrombosis.
Methods and Results: In this study we show that CAPs represent novel unconventional ligands for TLR9. Furthermore, using human and murine platelets, we demonstrate that CAPs 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 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.
- Received May 23, 2012.
- Accepted October 15, 2012.
- Copyright © 2012, American Heart Association