Platelet hyperreactivity, which is common in many pathological conditions, is associated with increased atherothrombotic risk. The mechanisms leading to platelet hyperreactivity are complex and not yet fully understood.
Platelet hyperreactivity and accelerated thrombosis, specifically in dyslipidemia, have been mechanistically linked to accumulation in the circulation of a specific group of oxidized phospholipids (oxPC CD36) that are ligands for the platelet pattern-recognition receptor CD36. In the current manuscript, we tested whether the platelet innate immune system contributes to responses to oxPC CD36 and accelerated thrombosis observed in hyperlipidemia.
Using in vitro approaches, as well as platelets from mice with genetic deletion of MyD88 or TLRs, we demonstrate that TLR2 and TLR6 are required for the activation of human and murine platelets by oxPC CD36. oxPC CD36 induce formation of CD36/TLR2/TLR6 complex in platelets and activate downstream signaling via TIRAP-MyD88-IRAK1/4-TRAF6, leading to integrin activation via the SFK-Syk-PLCγ2 pathway. Intravital thrombosis studies using ApoE −/− mice with genetic deficiency of TLR2 or TLR6 have demonstrated that oxPC CD36 contribute to accelerated thrombosis specifically in the setting of hyperlipidemia.