Desialylated Platelet Clearance in the Liver is a Novel Mechanism of Systemic Immunosuppression  

作　　者：June Li Danielle Karakas Feng Xue Yingyu Chen Guangheng Zhu Yeni H.Yucel Sonya A.MacParland Haibo Zhang John W.Semple John Freedman Qizhen Shi Heyu Ni 

机构地区：[1]Department of Laboratory Medicine and Pathobiology,University of Toronto,Toronto,ON,Canada [2]Toronto Platelet Immunobiology Group,Toronto,ON,Canada [3]Keenan Research Centre for Biomedical Science of St.Michael's Hospital,Toronto,ON,Canada [4]Canadian Blood Services Centre for Innovation,Toronto,ON,Canada [5]Departments of Pediatrics,Medical College of Wisconsin,Milwaukee,WI,USA [6]Blood Research Institute,Versiti Wisconsin,Milwaukee,WI,USA [7]Departments of Ophthalmology and Vision Sciences Medicine,University of Toronto,Toronto,ON,Canada [8]Faculty of Engineering and Architectural Science,Ryerson University,Toronto,ON,Canada [9]Multi-Organ Transplant Program,Toronto General Hospital Research Institute,Toronto,ON,Canada [10]Department of Immunology,University of Toronto,Toronto,ON,Canada [11]Critical Care Medicine,Department ofAnesthesiology and Pain,University of Toronto,Toronto,ON,Canada [12]Department of Physiology,University of Toronto,Toronto,ON,Canada [13]Department of Pharmacology,University of Toronto,Toronto,ON,Canada. [14]Division of Hematology and Transfusion Medicine,Lund University,Lund,Sweden [15]clinical Immunology and Transfusion Medicine,Ofice of Medical Services,Region Skane,Lund,Sweden [16]Department of Medicine,University of Toronto,Toronto,ON,Canada [17]Children's Research Institute,Children's Wisconsin,Wauwatosa,WI,USA [18]Midwest Athletes Against Childhood Cancer Fund Research Center,Milwaukee,WI,USA.

出　　处：《Research》2024年第3期35-50,共16页研究（英文）

基　　金：Canadian Institutes of Health Research Foundation grant (389035) (to H.N.);Canadian Institutes of Health Research (CIHR projects: MOP 97918 and MOP 119540) (to H.N.);CIHR-Canadian Blood Services Partnership (to H.N.);Canadian Blood Services Intramural Grant (to H.N.);the Canadian Foundation for Innovation (to H.N.);the National Institutes of Health, National Heart, Lung, and Blood Institute grant HL-102035 (to Q.S.);Midwest Athletes Against Childhood Cancer (MACC) Fund (to Q.S.);J.L. is a recipient of Graduate Fellowship from Canadian Blood Services Centre for Innovation, and D.K. is a recipient of a St. Michael's Hospital Research Training Centre (RTC) Scholarship, and Queen Elizabeth II (QE-II) Graduate Scholarship.

摘　　要：Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various disease states. However, the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored. Here, we uncovered, unexpectedly, desialylated platelets (dPLTs) down-regulated immune responses against both platelet-associated and -independent antigen challenges. Utilizing multispectral photoacoustic tomography, we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver, a process that we identified to be synergistically dependent on platelet glycoprotein Ibα and hepatic Ashwell–Morell receptor. Mechanistically, Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4+ regulatory T cells, abolishable by Kupffer cell depletion. Last, in a clinically relevant model of hemophilia A, presensitization with dPLT attenuated anti-factor VIII antibody production after factor VIII ( infusion. As platelet desialylation commonly occurs in daily-aged and activated platelets, these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.

关 键 词：PLATELET TRANSFUSION HOMEOSTASIS 

分 类 号：R575[医药卫生—消化系统]