Red Blood Cell Glycation Triggers In Vivo Cerebral Erythrophagocytosis in Adult Zebrafish in a Model Mimicking Hemorrhagic Stroke

Hemorrhagic stroke, particularly intracerebral hemorrhage (ICH), is a highly lethal subtype of stroke, responsible for a poor prognosis and a high rate of disability. ICH is characterized by the extravasation of red blood cells (RBCs) into the central nervous system. Efficient clearance of RBC lysis products is critical. Erythrophagocytosis may serve as a key protective mechanism in mitigating secondary damage of ICH. Interestingly, diabetes is known to promote RBC glycation and to exacerbate the consequences of ICH. However, the link between glycation, RBC clearance and neurological outcomes after ICH is not clear. In this study, we aimed to decipher the role of glycated RBCs in ICH. For this, we used human RBCs glycated by methylglyoxal (MGO), an intermediate product of glycolysis recognized as one of the most potent glycating agents in humans. These glycated RBCs displayed altered morphology, reduced deformability capacity and increased eryptosis. We then proceeded to RBC microinjection into the brain parenchyma of Tg(mpeg1.1:mCherry) zebrafish allowing the visualization of both microglia and macrophages. Although the presence of RBCs in the parenchyma did not affect the increased recruitment of mpeg1.1-positive cells to the injection site compared to vehicle injection, RBC glycation significantly enhanced erythrophagocytosis. In conclusion, we established an innovative model of ICH, and we demonstrated enhanced RBC phagocytosis in the brain under glycated conditions. Further research is needed to understand the consequence of such process in ICH damage. Finally, our model may contribute to the identification of specific neurorestorative therapeutics aimed at improving brain plasticity after stroke in diabetic context.