A role for activated endothelial cells in red blood cell clearance: implications for vasopathology

Abstract

The online version of this article has a Supplementary Appendix. BackgroundPhosphatidylserine 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 αv-integrin. Phagocytosis via the phosphatidylserine-lactadherin-αv-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes. Design and MethodsEndothelial 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. ResultsRed 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. ConclusionsActivated 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.

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

“…The bound RRx-001-modified RBCs, abundant in oxidized lipids, iron, and heme, are phagocytized by TAM [19,20], leading to their repolarization from M2-like to M1-like. As a result, the RRx-001-bound red blood cell resembles the 'Trojan Horse' of Greek mythology, bearing abundant free radicals in the form of iron, heme, and oxidized lipids, which leads to repolarization of the TAMs in the hypoxic tumor environment ( Figure 5(c)).…”

Polymeric stent materials dysregulate macrophage and endothelial cell functions: Implications for coronary artery stent

“…apoptosis bodies[35], senescent neutrophils[36] and red blood cells[37]. The phagocytosis of necrotic cells induces activation of ECs by releasing TGF-β1 and IL-6 [38, 39] and increases ICAM-1 expression to facilitate macrophage adhesion.…”

“…[40] In this scenario, phagocytosis dysreguates EC function and eventually leads to cell death. [37] ECs have also been shown to phagocytize polymer particles. [41-43] In contrast to enhanced macrophage phagocytosis, the phagocytic activity of ECs decreased upon microparticle treatment (Fig.…”

Phagocytosis of platelets enhances endothelial cell survival under serum deprivation

“…14,15,20 Endothelial cells possess a strong ability to engulf a variety of cell types. [21][22][23] Thus, it is reasonable that endothelial cells are considered ''non-professional phagocytes.'' 23 Similar to these reports, we found that endothelial cells derived from humans can engulf human platelets.…”