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P2X Receptor-Dependent Erythrocyte Damage by α-Hemolysin from Escherichia coli Triggers Phagocytosis by THP-1 Cells
Department of Biomedicine, Physiology, Aarhus University, Ole Worms Allé 4, 8000 Aarhus C, Building 1160, Aarhus 8000, Denmark
* Author to whom correspondence should be addressed.
Received: 7 January 2013; in revised form: 6 February 2013 / Accepted: 18 February 2013 / Published: 5 March 2013
Abstract: The pore-forming exotoxin α-hemolysin from E. coli causes a significant volume reduction of human erythrocytes that precedes the ultimate swelling and lysis. This shrinkage results from activation of Ca2+-sensitive K+ (KCa3.1) and Cl− channels (TMEM16A) and reduced functions of either of these channels potentiate the HlyA-induced hemolysis. This means that Ca2+-dependent activation of KCa3.1 and TMEM16A protects the cells against early hemolysis. Simultaneous to the HlyA-induced shrinkage, the erythrocytes show increased exposure of phosphatidylserine (PS) in the outer plasma membrane leaflet, which is known to be a keen trigger for phagocytosis. We hypothesize that exposure to HlyA elicits removal of the damaged erythrocytes by phagocytic cells. Cultured THP-1 cells as a model for erythrocytal phagocytosis was verified by a variety of methods, including live cell imaging. We consistently found the HlyA to very potently trigger phagocytosis of erythrocytes by THP-1 cells. The HlyA-induced phagocytosis was prevented by inhibition of KCa3.1, which is known to reduce PS-exposure in human erythrocytes subjected to both ionomycin and HlyA. Moreover, we show that P2X receptor inhibition, which prevents the cell damages caused by HlyA, also reduced that HlyA-induced PS-exposure and phagocytosis. Based on these results, we propose that erythrocytes, damaged by HlyA-insertion, are effectively cleared from the blood stream. This mechanism will potentially reduce the risk of intravascular hemolysis.
Keywords: phagocytosis; phosphatidyl serine; hemolysin E. coli; monocytes; hemolysis; P2X
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Fagerberg, S.K.; Skals, M.; Leipziger, J.; Praetorius, H.A. P2X Receptor-Dependent Erythrocyte Damage by α-Hemolysin from Escherichia coli Triggers Phagocytosis by THP-1 Cells. Toxins 2013, 5, 472-487.
Fagerberg SK, Skals M, Leipziger J, Praetorius HA. P2X Receptor-Dependent Erythrocyte Damage by α-Hemolysin from Escherichia coli Triggers Phagocytosis by THP-1 Cells. Toxins. 2013; 5(3):472-487.
Fagerberg, Steen K.; Skals, Marianne; Leipziger, Jens; Praetorius, Helle A. 2013. "P2X Receptor-Dependent Erythrocyte Damage by α-Hemolysin from Escherichia coli Triggers Phagocytosis by THP-1 Cells." Toxins 5, no. 3: 472-487.