Li June, Karakas Danielle, Xue Feng, Chen Yingyu, Zhu Guangheng, Yucel Yeni H, MacParland Sonya A, Zhang Haibo, Semple John W, Freedman John, Shi Qizhen, Ni Heyu
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Toronto Platelet Immunobiology Group, Toronto, ON, Canada.
Research (Wash D C). 2023 Oct 5;6:0236. doi: 10.34133/research.0236. eCollection 2023.
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.
血小板是体积小、功能多样的血细胞，对止血/血栓形成至关重要。局部血小板聚集是多种疾病状态下促炎症反应的已知因素。然而，血小板的抗炎/免疫抑制潜力尚未得到充分探索。在此，我们意外地发现，去唾液酸血小板（dPLT）可下调针对血小板相关和非相关抗原刺激的免疫反应。利用多光谱光声断层扫描技术，我们追踪了dPLT向肠道血管的转运以及肝脏中由库普弗细胞介导的dPLT特异性清除过程，我们发现该过程协同依赖于血小板糖蛋白Ibα和肝脏阿什韦尔-莫雷尔受体。从机制上讲，库普弗细胞对dPLT的清除增强了全身免疫抑制状态，伴随着抗炎细胞因子和循环CD4调节性T细胞增加，库普弗细胞耗竭可消除这种状态。最后，在一个临床相关的甲型血友病模型中，用dPLT进行预致敏可减弱因子VIII输注后抗因子VIII抗体的产生。由于血小板去唾液酸化常见于老化和活化的血小板中，这些发现为理解免疫稳态开辟了新途径，并增强了dPLT和工程化dPLT输血在控制自身免疫性和同种免疫性疾病方面的治疗潜力。
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