Research

Erythrocytes in metabolic steatohepatitis: At the crossroad of immunometabolism

Our group in collaboration with Prof. Dr Mimidis, has shown that erythrocytes of metabolic steatohepatitis patients exhibit increased "FIND ME" signals (increased MCP1 binding and release, but stable release of Sphingosine-1 phosphate), increased "EAT ME" signals (increased sphingosine, lactadherin, calreticulin, mannose binding lectin, but reduced Thrombospondin-1 levels), and reduced " DO NOT EAT ME" signals (reduced CD47). Importantly, we have shown that erythrocytes of metabolic steatohepatitis patients can induce macrophage activation in vitro, probably through MCP1 release. In addition, our results of increased erythrocyte TLR9 imply that erythrophagocytosis could result to the development of a specific pro-inflammatory erythrophagocyte subset.

We have tried to elaborate on the metabolic cues leading to erythrocyte dysfunction during metabolic steatohepatitis. Arginase-1, glutaminase-1 and adenosine monophosphate deaminase 3, are all implicated in the regulation of oxidative stress. However, our results show decreased arginase and increased glutaminase activity. Nevertheless, we have reported decreased sphingomyelin and increased sphingosine levels in erythrocytes of MAFLD patients. These metabolic changes could favor the generation of erythrophagocytosis signals.

Our results so far, indicate that systemic metabolic inflammation impacts erythrocytes; in turn metabolically abnormal red blood cells are tagged for elimination from the circulation. We hypothesize that once inside macrophages, red blood cells deposit their aberrant metabolome (augmented cholesterol, sphingosine and iron, reduced PC/PE and ornithine, and perhaps increased glucose and glutamine) resulting in ferroptosis and inflammation.

This research was funded by the Hellenic Foundation for Research and Innovation (31000 Euros) and is now funded by the Hellenic Association for the Study of the Liver (15000 Euros).

Erythrocytes in stroke: Real time biomarkers for immunometabolic crosstalk

We recently set out to explore the role of erythrocytes in prognosis of stroke. Based on previous findings regarding erythrocyte's dysfunction in atherosclerosis, we hypothesized that red blood cell membrane lipids, surface proteins and cytosolic enzymes could predict the prognosis in stroke patients. In particular, it has been previously shown that membrane cholesterol of erythrocytes contributes to the plaque's necrotic lipid core, CD47 and MCP1 regulate erythrocyte phagocytosis and, hence, cholesterol disposition, and arginase regulates vassorelaxation. Our study will firstly investigate the clinical value of these molecules. 

This research is funded by the European Development Regional Fund, and the principal investigator is Prof. Dr. Konstantinos Vadikolias.