Abstract
Background: Eryptosis is a physiological, apoptosis-like death of injured erythrocytes crucial to prevent premature haemolysis and the pathological sequalae generated by cell-free haemoglobin. When dysregulated, the process is associated to several inflammatory-based pathologies. 4-Hydroxy-trans-2-nonenal (HNE) is an endogenous signalling molecule at physiological levels and, at higher concentrations, is involved in the pathogenesis of several inflammatory-based diseases. This work evaluated whether HNE could induce eryptosis in human erythrocytes. Methods: Measurements of phosphatidylserine, cell volume, intracellular oxidants, Ca++, glutathione, ICAM-1, and ceramide were assessed by flow cytometry. Scanning electron microscopy evaluated morphological alterations of erythrocytes. Western blotting assessed caspases. PGE2 was measured by ELISA. Adhesion of erythrocytes on endothelial cells was evaluated by gravity adherence assay. Results: HNE in the concentration range between 10–100 µM induces eryptosis, morphological alterations correlated to caspase-3 activation, and increased Ca++ levels. The process is not mediated by redox-dependent mechanisms; rather, it strongly depends on PGE2 and ceramide. Interestingly, HNE induces significant increase of erythrocytes adhesion to endothelial cells (ECs) that are in turn dysfunctionated as evident by overexpression of ICAM-1. Conclusions: Our results unveil a new physiopathological role for HNE, provide mechanistic details of the HNE-induced eryptosis, and suggest a novel mechanism through which HNE could exert pro-inflammatory effects.
Highlights
Eryptosis is a physiological, apoptosis-like, suicidal death of erythrocytes (RBC) [1]
The process is not mediated by redox-dependent mechanisms; rather, it strongly depends on PGE2 and ceramide
Due to propensity of eryptotic RBC to adhere to endothelial cells (ECs), eryptosis has been involved in the pathogenesis of inflammatory and cardiometabolic diseases [3,4]
Summary
Apoptosis-like, suicidal death of erythrocytes (RBC) [1]. Hallmark of the eryptotic process is the loss of membrane phospholipid asymmetry due to the translocation of the cell membrane phospholipid phosphatidylserine (PS) from the inner to the outer leaflet by Ca++-sensitive scramblase [2]. This process allows eryptotic RBCs to be recognized by macrophages, phagocytosed, degraded, and cleared from circulation. Apoptosis-like death of injured erythrocytes crucial to prevent premature haemolysis and the pathological sequalae generated by cell-free haemoglobin. Results: HNE in the concentration range between 10–100 μM induces eryptosis, morphological alterations correlated to caspase-3 activation, and increased Ca++ levels. HNE induces significant increase of erythrocytes adhesion to endothelial cells (ECs) that are in turn dysfunctionated as evident by overexpression of ICAM-1. Conclusions: Our results unveil a new physiopathological role for HNE, provide mechanistic details of the HNE-induced eryptosis, and suggest a novel mechanism through which HNE could exert pro-inflammatory effects
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