Kaminski Tomasz W, Zhang Hong, Katoch Omika, Shi Qizhen, Kato Gregory J, Sundd Prithu, Pradhan-Sundd Tirthadipa
Hemostasis and Thrombosis Program, Versiti Blood Research Institute, Milwaukee, WI.
BioMagis Inc, San Diego, CA.
Blood Vessel Thromb Hemost. 2025 May;2(2). doi: 10.1016/j.bvth.2025.100045. Epub 2025 Jan 9.
Intrahepatic accumulation of cell-free hemoglobin (Hb) is a significant pathology linked with hemolytic disorders such as sickle cell disease (SCD). In addition to hepatic Kupffer cells, liver sinusoidal endothelial cells (LSECs) were recently reported to contribute to Hb clearance in SCD mice and patients via currently unknown endocytic mechanism. Using small-molecule inhibitors of endocytic pathway components in primary human and mouse LSECs, we show that sickle-Hb (HbS) uptake by LSECs occurs predominantly through micropinocytosis or fluid-phase endocytosis. However, inhibiting clathrin-mediated endocytosis, receptor recycling, or drop in pH also significantly attenuated HbS uptake by LSECs. LSEC-driven HbS uptake was independent of haptoglobin. Finally, we found that the presence of lipid droplets promotes endothelial HbS internalization, whereas hypolipidemic condition inhibits it. In conclusion, this study identifies previously unknown alternative mechanism of LSEC-mediated HbS internalization. Our findings also inform the need to evaluate the therapeutic potential of blocking these mechanisms to ameliorate hemolysis-associated liver damage in SCD and other hemolytic disorders.
无细胞血红蛋白（Hb）在肝内蓄积是一种与镰状细胞病（SCD）等溶血性疾病相关的重要病理现象。除了肝库普弗细胞外，最近有报道称肝窦内皮细胞（LSECs）通过目前未知的内吞机制参与SCD小鼠和患者体内Hb的清除。通过使用原代人和小鼠LSECs中内吞途径成分的小分子抑制剂，我们发现LSECs对镰状血红蛋白（HbS）的摄取主要通过微胞饮作用或液相内吞作用发生。然而，抑制网格蛋白介导的内吞作用、受体循环或pH值下降也显著减弱了LSECs对HbS的摄取。LSECs驱动的HbS摄取与触珠蛋白无关。最后，我们发现脂滴的存在促进内皮细胞对HbS的内化，而低脂血症状态则抑制这种内化。总之，本研究确定了LSECs介导HbS内化的先前未知的替代机制。我们的研究结果还表明，有必要评估阻断这些机制以改善SCD和其他溶血性疾病中与溶血相关的肝损伤的治疗潜力。
