Department of Clinical Chemistry and Hematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Utrecht, The Netherlands.
Haematologica. 2012 Apr;97(4):500-8. doi: 10.3324/haematol.2011.048694. Epub 2011 Nov 18.
Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and α(v)-integrin. Phagocytosis via the phosphatidylserine-lactadherin-α(v)-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes.
Endothelial cell phagocytosis of red blood cells was further explored using a more (patho)physiological approach. Red blood cells were exposed to oxidative stress, induced by tert-butyl hydroperoxide. After opsonization with lactadherin, red blood cells were incubated with endothelial cells to study erythrophagocytosis and examine cytotoxicity.
Red blood cells exposed to oxidative stress show alterations such as phosphatidylserine exposure and loss of deformability. When incubated with endothelial cells, marked erythrophagocytosis occurred in the presence of lactadherin under both static and flow conditions. As a consequence, intracellular organization was disturbed and endothelial cells were seen to change shape ('rounding up'). Increased expression of apoptotic markers indicated that marked erythrophagocytosis has cytotoxic effects.
Activated endothelial cells show significant phagocytosis of phosphatidylserine-exposing and rigid red blood cells under both static and flow conditions. This results in a certain degree of cytotoxicity. We postulate that activated endothelial cells play a role in red blood cell clearance in vivo. Significant erythrophagocytosis can induce endothelial cell loss, which may contribute to vasopathological effects as seen, for instance, in sickle cell disease.
红细胞暴露磷脂酰丝氨酸被认为是启动细胞从循环中被吞噬清除的信号。已知几种疾病和情况会诱导磷脂酰丝氨酸暴露。带磷脂酰丝氨酸的红细胞通常由脾脏和肝脏中的巨噬细胞清除。然而，此前我们已经表明内皮细胞也能够吞噬红细胞。内皮细胞吞噬红细胞的关键参与者似乎是乳黏蛋白和α(v)整合素。通过磷脂酰丝氨酸-乳黏蛋白-α(v)整合素途径的吞噬作用被认为是吞噬细胞清除凋亡固有细胞的公认途径。
使用更（病理）生理的方法进一步探索内皮细胞对红细胞的吞噬作用。用叔丁基过氧化物诱导红细胞产生氧化应激，然后用乳黏蛋白调理，再与内皮细胞孵育以研究红细胞吞噬作用并检测细胞毒性。
暴露于氧化应激的红细胞会发生磷脂酰丝氨酸暴露和变形能力丧失等改变。在用乳黏蛋白调理后，在静态和流动条件下，与内皮细胞孵育时，会发生明显的红细胞吞噬作用。结果，细胞内结构受到干扰，内皮细胞的形状发生改变（“变圆”）。凋亡标志物表达增加表明明显的红细胞吞噬作用具有细胞毒性作用。
在静态和流动条件下，激活的内皮细胞对带磷脂酰丝氨酸的刚性红细胞具有显著的吞噬作用。这会导致一定程度的细胞毒性。我们推测激活的内皮细胞在体内的红细胞清除中起作用。明显的红细胞吞噬作用会导致内皮细胞丢失，这可能导致血管病理效应，例如在镰状细胞病中所见。
