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

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

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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.

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

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Department of Laboratory Medicine and Pathobiology,University of Toronto,Toronto,ON,Canada

Toronto Platelet Immunobiology Group,Toronto,ON,Canada

Keenan Research Centre for Biomedical Science of St.Michael's Hospital,Toronto,ON,Canada

Canadian Blood Services Centre for Innovation,Toronto,ON,Canada

Departments of Pediatrics,Medical College of Wisconsin,Milwaukee,WI,USA

Blood Research Institute,Versiti Wisconsin,Milwaukee,WI,USA

Departments of Ophthalmology and Vision Sciences Medicine,University of Toronto,Toronto,ON,Canada

Faculty of Engineering and Architectural Science,Ryerson University,Toronto,ON,Canada

Multi-Organ Transplant Program,Toronto General Hospital Research Institute,Toronto,ON,Canada

Department of Immunology,University of Toronto,Toronto,ON,Canada

Critical Care Medicine,Department of Anesthesiology and Pain,University of Toronto,Toronto,ON,Canada

Department of Physiology,University of Toronto,Toronto,ON,Canada

Department of Pharmacology,University of Toronto,Toronto,ON,Canada

Division of Hematology and Transfusion Medicine,Lund University,Lund,Sweden

Clinical Immunology and Transfusion Medicine,Office of Medical Services,Region Skåne,Lund,Sweden

Department of Medicine,University of Toronto,Toronto,ON,Canada

Children's Research Institute,Children's Wisconsin,Wauwatosa,WI,USA

Midwest Athletes Against Childhood Cancer Fund Research Center,Milwaukee,WI,USA

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2024

研究(英文)

研究(英文)

CSTPCD
ISSN:
年,卷(期):2024.2024(3)