Membrane bending and sphingomyelinase-associated, sulfatide-dependent hypoxic adhesion of sickle mature erythrocytes.
Membrane bending and sphingomyelinase-associated, sulfatide-dependent hypoxic adhesion of sickle mature erythrocytes.
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DOI：
10.1182/bloodadvances.2022008392
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发表时间：
2023-05-23
期刊：
影响因子：
7.5
通讯作者：
Gurkan, Umut A.
中科院分区：
文献类型：
--
作者：
Goreke, Utku;Kucukal, Erdem;Wang, Fang;An, Ran;Arnold, Nicole;Quinn, Erina;Yuan, Charlotte;Bode, Allison;Hill, Ailis;Man, Yuncheng;Hambley, Bryan C.;Schilz, Robert;Ginwalla, Mahazarin;Little, Jane A.;Gurkan, Umut A.
镰状血红蛋白聚合对质膜施加的弯曲应力增强了 SCD 中硫苷脂介导的成熟红细胞的粘附。炎症性鞘磷脂酶活性可能导致镰状成熟红细胞异常粘附和膜损伤。镰状血红蛋白聚合导致的红细胞粘附异常是镰状细胞病 (SCD) 病理生理学的核心。成熟红细胞占 SCD 中所有红细胞的 80% 以上；然而，红细胞对 SCD 急性和慢性血管病变的相对作用尚不清楚。在这里，我们发现，缺氧下镰状血红蛋白聚合对红细胞质膜施加弯曲应力，增强硫脑苷脂介导的异常成熟红细胞粘附。我们假设鞘磷脂酶（SMase）活性通过累积弯曲能量而上调，导致膜硫苷脂可用性升高，从而导致缺氧的成熟红细胞粘附。我们发现，在受控微流体实验中，成熟红细胞对层粘连蛋白的粘附力在缺氧条件下明显高于常氧条件下（1856 ± 481 vs 78 ± 23，平均值± SEM），而镰状网织红细胞（早期红细胞）粘附力一开始就很高，但没有改变（1281 ± 299 vs 1258 ± 328，平均值± SEM）。我们发现，粘附的成熟红细胞的平均累积弯曲能越大，与酸性 SMase 活性越高和成熟红细胞粘附力增加相关（对于酸性 SMase 活性，P = .022；对于缺氧时成熟红细胞粘附力的增加，P = .002，N = 5）。此外，缺氧导致红细胞膜硫苷脂暴露，SMase增加，而抗硫苷脂抑制红细胞粘附增强。这些结果表明质膜的脂质成分导致 SCD 并发症。因此，硫脑苷脂及其上调途径的成分，特别是SMase，应该进一步探索作为抑制镰状红细胞粘附的潜在治疗靶点。
Bending stress exerted on the plasma membrane by sickle hemoglobin polymerization enhances sulfatide-mediated adhesion of mature erythrocytes in SCD. Inflammatory sphingomyelinase activity could result in abnormal adhesion and membrane damage in sickle mature erythrocytes. Abnormal erythrocyte adhesion owing to polymerization of sickle hemoglobin is central to the pathophysiology of sickle cell disease (SCD). Mature erythrocytes constitute >80% of all erythrocytes in SCD; however, the relative contributions of erythrocytes to acute and chronic vasculopathy in SCD are not well understood. Here, we showed that bending stress exerted on the erythrocyte plasma membrane by polymerization of sickle hemoglobin under hypoxia, enhances sulfatide-mediated abnormal mature erythrocyte adhesion. We hypothesized that sphingomyelinase (SMase) activity, which is upregulated by accumulated bending energy, leads to elevated membrane sulfatide availability, and thus, hypoxic mature erythrocyte adhesion. We found that mature erythrocyte adhesion to laminin in controlled microfluidic experiments is significantly greater under hypoxia than under normoxia (1856 ± 481 vs 78 ± 23, mean ± SEM), whereas sickle reticulocyte (early erythrocyte) adhesion, high to begin with, does not change (1281 ± 299 vs 1258 ± 328, mean ± SEM). We showed that greater mean accumulated bending energy of adhered mature erythrocytes was associated with higher acid SMase activity and increased mature erythrocyte adhesion (P = .022, for acid SMase activity and P = .002 for the increase in mature erythrocyte adhesion with hypoxia, N = 5). In addition, hypoxia results in sulfatide exposure of the erythrocyte membrane, and an increase in SMase, whereas anti-sulfatide inhibits enhanced adhesion of erythrocytes. These results suggest that the lipid components of the plasma membrane contribute to SCD complications. Therefore, sulfatide and the components of its upregulation pathway, particularly SMase, should be further explored as potential therapeutic targets for inhibiting sickle erythrocyte adhesion.
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