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.

Full text not available from this repository.
Item Type: Article
Status: Published
Official URL: https://doi.org/10.1161/CIRCULATIONAHA.118.036323
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
Abstract:

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.

Creators:
Creators
Email
Li, Jing
UNSPECIFIED
Kim, Kyungho
UNSPECIFIED
Jeong, Si-Yeon
UNSPECIFIED
Chiu, Joyce
UNSPECIFIED
Xiong, Bei
UNSPECIFIED
Petukhov, Pavel A.
UNSPECIFIED
Dai, Xiangrong
UNSPECIFIED
Li, Xiaoyi
UNSPECIFIED
Andrews, Robert K.
UNSPECIFIED
Du, Xiaoping
UNSPECIFIED
Hogg, Philip J.
UNSPECIFIED
Cho, Jaehyung
UNSPECIFIED
Last Modified: 17 Dec 2020 03:27
URI: https://eprints.centenary.org.au/id/eprint/259

Actions (login required)

View Item View Item