Platelet Activation and Thrombus Formation over IgG Immune Complexes Requires Integrin αIIbβ3 and Lyn Kinase.
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.
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States of America.
Huiying
H
Zhi
Ruijing Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Jing
J
Dai
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Junling
J
Liu
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States of America; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Jieqing
J
Zhu
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States of America; Department of Microbiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Debra K
DK
Newman
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States of America; Chronic Disease Research Institute, Department of Nutrition and Food Hygiene, Zhejiang University School of Public Health, Hangzhou, China.
Cunji
C
Gao
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States of America; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Department of Cell biology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Peter J
PJ
Newman
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001327:Autoimmune Diseases / Q000378:metabolism / Q000503:physiopathology; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation / Q000502:physiology*; D010973:Platelet Adhesiveness / Q000502:physiology; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013927:Thrombosis / Q000378:metabolism* / Q000503:physiopathology*; D019061:src-Family Kinases / Q000378:metabolism*
D000936:Antigen-Antibody Complex; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D017452:Receptors, IgG; C094990:adhesion receptor; D005340:Fibrinogen; D011505:Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases