Platelet Protein Disulfide Isomerase Promotes Glycoprotein Ibα–Mediated Platelet-Neutrophil Interactions Under Thromboinflammatory Conditions

Platelet Protein Disulfide Isomerase Promotes Glycoprotein Ibα–Mediated Platelet-Neutrophil Interactions Under Thromboinflammatory Conditions.

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Circulation
Volume: 139
Number: 10
Page Range: pp. 1300-1319
Date: 2019
Divisions: ACRF Centenary Cancer Research Centre
Depositing User: General Admin
Identification Number: 10.1161/CIRCULATIONAHA.118.036323
ISSN: 0009-7322
Date Deposited: 17 Dec 2020 03:27

Background: Platelet-neutrophil interactions contribute to vascular occlusion and tissue damage in thromboinflammatory disease. Platelet glycoprotein Ibα (GPIbα), a key receptor for the cell-cell interaction, is believed to be constitutively active for ligand binding. Here, we established the role of platelet-derived protein disulfide isomerase (PDI) in reducing the allosteric disulfide bonds in GPIbα and enhancing the ligand-binding activity under thromboinflammatory conditions.

Methods: Bioinformatic analysis identified 2 potential allosteric disulfide bonds in GPIbα. Agglutination assays, flow cytometry, surface plasmon resonance analysis, a protein-protein docking model, proximity ligation assays, and mass spectrometry were used to demonstrate a direct interaction between PDI and GPIbα and to determine a role for PDI in regulating GPIbα function and platelet-neutrophil interactions. Also, real-time microscopy and animal disease models were used to study the pathophysiological role of PDI-GPIbα signaling under thromboinflammatory conditions.

Results: Deletion or inhibition of platelet PDI significantly reduced GPIbα-mediated platelet agglutination. Studies using PDI-null platelets and recombinant PDI or Anfibatide, a clinical-stage GPIbα inhibitor, revealed that the oxidoreductase activity of platelet surface-bound PDI was required for the ligand-binding function of GPIbα. PDI directly bound to the extracellular domain of GPIbα on the platelet surface and reduced the Cys4-Cys17 and Cys209-Cys248 disulfide bonds. Real-time microscopy with platelet-specific PDI conditional knockout and sickle cell disease mice demonstrated that PDI-regulated GPIbα function was essential for platelet-neutrophil interactions and vascular occlusion under thromboinflammatory conditions. Studies using a mouse model of ischemia/reperfusion-induced stroke indicated that PDI-GPIbα signaling played a crucial role in tissue damage.

Conclusions: Our results demonstrate that PDI-facilitated cleavage of the allosteric disulfide bonds tightly regulates GPIbα function, promoting platelet-neutrophil interactions, vascular occlusion, and tissue damage under thromboinflammatory conditions.

Keywords: blood platelets; glycoprotein Ibalpha; inflammation; neutrophils; protein disulfide isomerase.

Li, Jing
Kim, Kyungho
Jeong, Si-Yeon
Chiu, Joyce
Xiong, Bei
Petukhov, Pavel A.
Dai, Xiangrong
Li, Xiaoyi
Andrews, Robert K.
Du, Xiaoping
Hogg, Philip J.
Cho, Jaehyung
Last Modified: 17 Dec 2020 03:27

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