Faculty Collaboration Database

Platelet Activation and Thrombus Formation over IgG Immune Complexes Requires Integrin αIIbβ3 and Lyn Kinase. PLoS One 2015;10(8):e0135738

Date

08/21/2015

Pubmed ID

26291522

Pubmed Central ID

PMC4546160

DOI

10.1371/journal.pone.0135738

Scopus ID

2-s2.0-84942901879 (requires institutional sign-in at Scopus site)   28 Citations

Abstract

IgG immune complexes contribute to the etiology and pathogenesis of numerous autoimmune disorders, including heparin-induced thrombocytopenia, systemic lupus erythematosus, rheumatoid- and collagen-induced arthritis, and chronic glomerulonephritis. Patients suffering from immune complex-related disorders are known to be susceptible to platelet-mediated thrombotic events. Though the role of the Fc receptor, FcγRIIa, in initiating platelet activation is well understood, the role of the major platelet adhesion receptor, integrin αIIbβ3, in amplifying platelet activation and mediating adhesion and aggregation downstream of encountering IgG immune complexes is poorly understood. The goal of this investigation was to gain a better understanding of the relative roles of these two receptor systems in immune complex-mediated thrombotic complications. Human platelets, and mouse platelets genetically engineered to differentially express FcγRIIa and αIIbβ3, were allowed to interact with IgG-coated surfaces under both static and flow conditions, and their ability to spread and form thrombi evaluated in the presence and absence of clinically-used fibrinogen receptor antagonists. Although binding of IgG immune complexes to FcγRIIa was sufficient for platelet adhesion and initial signal transduction events, platelet spreading and thrombus formation over IgG-coated surfaces showed an absolute requirement for αIIbβ3 and its ligands. Tyrosine kinases Lyn and Syk were found to play key roles in IgG-induced platelet activation events. Taken together, our data suggest a complex functional interplay between FcγRIIa, Lyn, and αIIbβ3 in immune complex-induced platelet activation. Future studies may be warranted to determine whether patients suffering from immune complex disorders might benefit from treatment with anti-αIIbβ3-directed therapeutics.

Author List

Zhi H, Dai J, Liu J, Zhu J, Newman DK, Gao C, Newman PJ

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Peter J. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Jieqing Zhu PhD Assistant Professor, Associate Investigator in the Biochemistry department at BloodCenter of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antigen-Antibody Complex
Autoimmune Diseases
Blood Platelets
CHO Cells
Cell Line
Cricetulus
Fibrinogen
Humans
Immunoglobulin G
Mice
Mice, Inbred C57BL
Platelet Activation
Platelet Adhesiveness
Platelet Aggregation
Platelet Glycoprotein GPIIb-IIIa Complex
Platelet Glycoprotein GPIb-IX Complex
Protein-Tyrosine Kinases
Receptors, IgG
Signal Transduction
Thrombosis
src-Family Kinases