Wraith, K.S. orcid.org/0009-0000-7515-8492, Khalil, J.S., Aburima, A. et al. (11 more authors) (2025) The immune receptor FcRg-chain mediates CD36-induced platelet activation and thrombosis by oxidised low-density lipoproteins. Blood Advances. ISSN: 2473-9537
Abstract
The scavenger receptor CD36 links atherogenic dyslipidaemia to platelet hyperactivity and accelerated thrombosis through the binding of oxidised low-density lipoproteins (oxLDL). The signalling 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) adaptor proteins in CD36-mediated platelet activity. OxLDL induced the phosphorylation of the ITAM-containing adaptor FcRg-chain (FcRg) in human and murine platelets. Phosphorylation of FcRg was blocked by Src Family Kinase (SFK) inhibitors, mimicked by CD36-specific oxidised phospholipids and ablated in CD36-/- murine platelets. Under basal conditions, a pool of CD36 formed a multiprotein complex that included FcRg 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-FcRg complex, we used murine platelets deficient in FcRg. The genetic ablation of FcRg 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 FcRg. This study establishes FcRg as a first functional co-receptor for CD36 in platelets, which enables lipid platelet hyperactivity and arterial thrombosis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 American Society of Hematology. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY-NC-ND 4.0). |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation Accounts Payable - Gloria Sankey RG/16/5/32250 British Heart Foundation Accounts Payable - Gloria Sankey RG/F/22/110067 |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Jul 2025 09:07 |
Last Modified: | 25 Jul 2025 09:07 |
Status: | Published online |
Publisher: | American Society of Hematology (ASH Publications) |
Identification Number: | 10.1182/bloodadvances.2024015652 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:229592 |