OBJECTIVE: A novel mechanism of platelet destruction involving the CD47/ signal regulatory protein-α (SIRPα) system has recently been suggested in a mouse model of immune thrombocytopenia (ITP). The CD47 molecule serves as ligand for SIRPα receptor and as receptor for thrombospondin acting as antagonistic to phagocyte activity and a regulator of apoptosis, respectively. In this study, we evaluated if the CD47/SIRPα axis may be involved in the apoptosis and clearance of platelets in human ITP. MATERIALS AND METHODS: Using flow cytometry, we characterized whether expression of CD47 on fresh and in vitro-aged platelets- and of SIRPα receptor on CD14-derived dendritic cells (DCs), macrophages, circulating DCs, and monocytes is reduced is ITP; whether the in vitro platelet phagocytic capacity of CD14-derived DCs and macrophages is differentially modulated in the presence or absence of antibodies against CD47 and SIRPα in ITP; and whether platelets are more susceptible to the CD47-induced death signal in ITP. RESULTS: We demonstrated that low platelet count in ITP is not due to increased phagocytosis associated with decreased expression of CD47 on the platelet surface and, despite reduced SIRPα expression, blockage of SIRPα on immature CD14-derived DCs or CD47 on platelets by specific antibodies failed to modify platelet uptake/phagocytosis of DCs. In contrast, targeting platelet CD47 with specific antibody significantly increases platelet phagocytosis of CD14-derived macrophages, and platelets are not healthy because they show increased apoptosis and are resistant to CD47-induced death signal. CONCLUSIONS: Our results demonstrate that the CD47 pathway in ITP patients abnormally modulates platelet homeostasis.
OBJECTIVE: A novel mechanism of platelet destruction involving the CD47/ signal regulatory protein-α (SIRPα) system has recently been suggested in a mouse model of immune thrombocytopenia (ITP). The CD47 molecule serves as ligand for SIRPα receptor and as receptor for thrombospondin acting as antagonistic to phagocyte activity and a regulator of apoptosis, respectively. In this study, we evaluated if the CD47/SIRPα axis may be involved in the apoptosis and clearance of platelets in human ITP. MATERIALS AND METHODS: Using flow cytometry, we characterized whether expression of CD47 on fresh and in vitro-aged platelets- and of SIRPα receptor on CD14-derived dendritic cells (DCs), macrophages, circulating DCs, and monocytes is reduced is ITP; whether the in vitro platelet phagocytic capacity of CD14-derived DCs and macrophages is differentially modulated in the presence or absence of antibodies against CD47 and SIRPα in ITP; and whether platelets are more susceptible to the CD47-induced death signal in ITP. RESULTS: We demonstrated that low platelet count in ITP is not due to increased phagocytosis associated with decreased expression of CD47 on the platelet surface and, despite reduced SIRPα expression, blockage of SIRPα on immature CD14-derived DCs or CD47 on platelets by specific antibodies failed to modify platelet uptake/phagocytosis of DCs. In contrast, targeting platelet CD47 with specific antibody significantly increases platelet phagocytosis of CD14-derived macrophages, and platelets are not healthy because they show increased apoptosis and are resistant to CD47-induced death signal. CONCLUSIONS: Our results demonstrate that the CD47 pathway in ITP patients abnormally modulates platelet homeostasis.
Authors: Chun-Yan Wang; Sai Ma; Shao-Jie Bi; Le Su; Shu-Ya Huang; Jun-Ying Miao; Chun-Hong Ma; Cheng-Jiang Gao; Ming Hou; Jun Peng Journal: Ann Transl Med Date: 2019-04
Authors: John D Eicher; Nathalie Chami; Tim Kacprowski; Akihiro Nomura; Ming-Huei Chen; Lisa R Yanek; Salman M Tajuddin; Ursula M Schick; Andrew J Slater; Nathan Pankratz; Linda Polfus; Claudia Schurmann; Ayush Giri; Jennifer A Brody; Leslie A Lange; Ani Manichaikul; W David Hill; Raha Pazoki; Paul Elliot; Evangelos Evangelou; Ioanna Tzoulaki; He Gao; Anne-Claire Vergnaud; Rasika A Mathias; Diane M Becker; Lewis C Becker; Amber Burt; David R Crosslin; Leo-Pekka Lyytikäinen; Kjell Nikus; Jussi Hernesniemi; Mika Kähönen; Emma Raitoharju; Nina Mononen; Olli T Raitakari; Terho Lehtimäki; Mary Cushman; Neil A Zakai; Deborah A Nickerson; Laura M Raffield; Rakale Quarells; Cristen J Willer; Gina M Peloso; Goncalo R Abecasis; Dajiang J Liu; Panos Deloukas; Nilesh J Samani; Heribert Schunkert; Jeanette Erdmann; Myriam Fornage; Melissa Richard; Jean-Claude Tardif; John D Rioux; Marie-Pierre Dube; Simon de Denus; Yingchang Lu; Erwin P Bottinger; Ruth J F Loos; Albert Vernon Smith; Tamara B Harris; Lenore J Launer; Vilmundur Gudnason; Digna R Velez Edwards; Eric S Torstenson; Yongmei Liu; Russell P Tracy; Jerome I Rotter; Stephen S Rich; Heather M Highland; Eric Boerwinkle; Jin Li; Ethan Lange; James G Wilson; Evelin Mihailov; Reedik Mägi; Joel Hirschhorn; Andres Metspalu; Tõnu Esko; Caterina Vacchi-Suzzi; Mike A Nalls; Alan B Zonderman; Michele K Evans; Gunnar Engström; Marju Orho-Melander; Olle Melander; Michelle L O'Donoghue; Dawn M Waterworth; Lars Wallentin; Harvey D White; James S Floyd; Traci M Bartz; Kenneth M Rice; Bruce M Psaty; J M Starr; David C M Liewald; Caroline Hayward; Ian J Deary; Andreas Greinacher; Uwe Völker; Thomas Thiele; Henry Völzke; Frank J A van Rooij; André G Uitterlinden; Oscar H Franco; Abbas Dehghan; Todd L Edwards; Santhi K Ganesh; Sekar Kathiresan; Nauder Faraday; Paul L Auer; Alex P Reiner; Guillaume Lettre; Andrew D Johnson Journal: Am J Hum Genet Date: 2016-06-23 Impact factor: 11.043