RRC ID 82152
Author Tsukiji N, Yokomori R, Takusagawa K, Shirai T, Oishi S, Sasaki T, Takano K, Suzuki-Inoue K.
Title C-type lectin-like receptor-2 in platelets mediates ferric chloride-induced platelet activation and attenuates ferroptosis of endothelial cells.
Journal J Thromb Haemost
Abstract BACKGROUND:An iron overload status induces ferroptosis, an iron-dependent nonapoptotic cell death, in various pathological conditions. We previously reported that hemin (heme), protoporphyrin-IX with ferric iron, activates platelets via C-type lectin-like receptor-2 (CLEC-2) and glycoprotein VI/FcRγ, but protoporphyrin-IX alone blocks CLEC-2-dependent platelet activation. Therefore, we hypothesized that free iron has the ability to activate platelets.
OBJECTIVES:This study aimed to elucidate platelet activation mechanisms of iron (ferric chloride), including the identification of signaling pathways and receptors, and to examine whether platelets regulate ferroptosis.
METHODS:Platelet aggregometry, platelet activation marker expression, and protein phosphorylation were examined in ferric chloride-stimulated human and murine platelets. Inhibitors of platelet activation signaling pathways and receptor-deleted platelets were utilized to identify the responsible signaling pathway and receptor. The effect of platelets on ferroptosis of endothelial cells was investigated in vitro.
RESULTS:Ferric chloride induced platelet activation dependent on Src family kinase pathways in humans and mice. Ferric chloride-induced platelet aggregation was almost lost in CLEC-2-depleted murine platelets and wild-type platelets preincubated with recombinant CLEC-2 proteins. Furthermore, coculture of wild-type platelets, but not CLEC-2-deficient platelets, attenuated ferroptosis of endothelial cells in vitro.
CONCLUSION:Ferric chloride activates platelets via CLEC-2 and Src family kinase pathways, and platelets have a protective role in the ferroptosis of endothelial cells dependent on CLEC-2.
Volume 22(6)
Pages 1749-1757
Published 2024-6-1
DOI 10.1016/j.jtha.2024.03.003
PII S1538-7836(24)00160-0
PMID 38811291
MeSH Animals Blood Platelets* / drug effects Blood Platelets* / metabolism Chlorides* / metabolism Endothelial Cells / drug effects Endothelial Cells / metabolism Ferric Compounds* / pharmacology Ferroptosis* / drug effects Human Umbilical Vein Endothelial Cells / metabolism Humans Lectins, C-Type* / metabolism Mice Mice, Inbred C57BL* Mice, Knockout Phosphorylation Platelet Activation* / drug effects Platelet Aggregation* / drug effects Signal Transduction* src-Family Kinases / metabolism
Resource
Human and Animal Cells MAEC(RCB2712)