Plasma microparticles of sickle patients during crisis or taking hydroxyurea modify endothelium inflammatory properties

Abstract

<jats:title>Abstract</jats:title> <jats:p>Microparticles (MPs) are submicron extracellular vesicles exposing phosphatidylserine (PS), detected at high concentration in the circulation of sickle cell anemia (SS) patients. Several groups studied the biological effects of MPs generated ex vivo. Here, we analyzed for the first time the impact of circulating MPs on endothelial cells (ECs) from 60 sickle cell disease (SCD) patients. MPs were collected from SCD patients and compared with MPs isolated from healthy individuals (AA). Other plasma MPs were purified from SS patients before and 2 years after the onset of hydroxyurea (HU) treatment or during a vaso-occlusive crisis and at steady-state. Compared with AA MPs, SS MPs increased EC ICAM-1 messenger RNA and protein levels, as well as neutrophil adhesion. We showed that ICAM-1 overexpression was primarily caused by MPs derived from erythrocytes, rather than from platelets, and that it was abolished by MP PS capping using annexin V. MPs from SS patients treated with HU were less efficient to induce a proinflammatory phenotype in ECs compared with MPs collected before therapy. In contrast, MPs released during crisis increased ICAM-1 and neutrophil adhesion levels, in a PS-dependent manner, compared with MPs collected at steady-state. Furthermore, neutrophil adhesion was abolished by a blocking anti–ICAM-1 antibody. Our study provides evidence that MPs play a key role in SCD pathophysiology by triggering a proinflammatory phenotype of ECs. We also uncover a new mode of action for HU and identify potential therapeutics: annexin V and anti–ICAM-1 antibodies.</jats:p>

Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia

“…Compared to AA RBC-MPs, RBC-MPs from SCA patients increased the expression of adhesion molecules (ICAM-1 and E-selectin) in human aortic endothelial cells, indicating higher cell activation. These findings are in agreement with a recent study showing an impact of SCA RBC-MPs on microcirculation endothelial cells phenotype ( 67 ). ICAM-1 and E-selectin are implicated in circulating cell interactions with the endothelium, which contribute to vascular dysfunction ( 68 ).…”

“…Garnier et al. recently showed that the deleterious effects of SCA MPs on endothelial cells were mediated by the PS exposure on their surface ( 67 ). Evaluating the specific phenotype of RBC-MPs from SCA patients could help in better understanding the mechanisms involved in their deleterious effects on endothelial function.…”

Circulating Extracellular Vesicles and Endothelial Damage in Sickle Cell Disease

“…These changes may be caused by transfer of heme contained in microparticles to endothelial cells. Microparticles released during vaso-occlusive crises increase endothelial ICAM-1 levels and neutrophil adhesion (Garnier et al, 2020). A recent study emphasizes the importance of platelet EVs in the pathogenesis of SCD.…”

Sickle cell disease and COVID‐19: Atypical presentations and favorable outcomes

“…Hydroxyurea has been used for more than 10 years in Europe and has changed the prognostic of sickle cell patients [15]. Hydroxyurea not only augments both HbF level and red blood cell deformability but also maintains the endothelium and Neutrophils Extracellular Traps (NET) equilibrium, and impacts the release of microparticles [16]. In the French registry, in patients with the worst outcome, age was mentioned as the most relevant risk factor but the mean dosage of Hydroxurea in those patients was also low and could have been a confounding factor [6].…”