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김경호
김경호 (Kyungho Kim) 저자 이메일 보기
한국한의학연구원, University of Illinois College of Medicine
 
조회 404  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Platelet Protein Disulfide Isomerase Promotes Glycoprotein Ibα–Mediated Platelet-Neutrophil Interactions Under Thromboinflammatory Conditions
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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.

Key Words : blood platelets, glycoprotein Ibalpha, inflammation, neutrophils, protein disulfide, isomerase

논문정보
- 형식: Research article
- 게재일: 2018년 11월 (BRIC 등록일 2019-03-06)
- 연구진: 국내+국외 연구진
- 분야: Medicine
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