The immune receptor FcRγ-chain mediates CD36-induced platelet activation and thrombosis by oxidized low-density lipoproteins.

abstractThe scavenger receptor CD36 links atherogenic dyslipidemia to platelet hyperactivity and accelerated thrombosis through the binding of oxidized low-density lipoproteins (oxLDL). The signaling mechanism(s) that facilitates CD36 translation of oxidative lipid stress into platelet activation is unclear. We examined the role of immunoreceptor tyrosine-based activation motif (ITAM) adapter proteins in CD36-mediated platelet activity. oxLDL induced the phosphorylation of the ITAM-containing adapter Fc receptor γ-chain (FcRγ) in human and murine platelets. Phosphorylation of FcRγ was blocked by Src family kinase (SFK) inhibitors, mimicked by CD36-specific oxidized phospholipids and ablated in CD36-/- murine platelets. Under basal conditions, a pool of CD36 formed a multiprotein complex that included FcRγ and the SFKs Lyn and Fyn. CD36 ligation by oxLDL resulted in the recruitment, phosphorylation, and activation of the tyrosine kinase Syk. To explore the functional cooperativity of this CD36-FcRγ complex, we used murine platelets deficient in FcRγ. The genetic ablation of FcRγ prevented oxLDL-induced tyrosine phosphorylation of Syk and downstream adapter SLP-76, but not SFKs. Moreover, platelet aggregation, in vitro thrombosis, and in vivo carotid thrombosis stimulated by oxLDL were lost in the absence of FcRγ. This study establishes FcRγ as a first functional coreceptor for CD36 in platelets, which enables lipid platelet hyperactivity and arterial thrombosis.