Desialylated Platelet Clearance in the Liver is a Novel Mechanism of Systemic Immunosuppression.
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
Author Information
June Li: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Danielle Karakas: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Feng Xue: Departments of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Yingyu Chen: Departments of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Guangheng Zhu: Toronto Platelet Immunobiology Group, Toronto, ON, Canada.
Yeni H Yucel: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada.
Sonya A MacParland: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Haibo Zhang: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada.
John W Semple: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
John Freedman: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Qizhen Shi: Departments of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Heyu Ni: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. ORCID
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.
