Major findings
Metabolic dysfunction associated fatty liver disease
Increased hepatic erythrophagocytosis and subsequent hepatic iron accumulation-induced ferroptosis is implicated in the pathogenesis of Metabolic inflammation of the Liver. Studies on animal models showed that erythrophagocytosis is caused by phosphatidylserine exposure on red blood cells. However, we have excluded the erythrocyte phosphatidylserine opsonization by calreticulin, lactadherin, mannose binding lectin and thrombospondin-1 in human metabolic inflammation of the Liver. Instead our work has shown that in human MAFLD, erythrocytes are phagocytosed through reduced CD47, increased MCP1 release, reduced phospholipid fluidity and increased sphingosine levels without changes in the release of sphingosine phosphate. We have also shown that in part these changes in MAFLD erythrocytes are driven by increased arginase-1 activity, and TLR9-induced cholesterol accumulation.
Dementia
Previous studies on animals models showed that oxidative stress-induced erythrocyte phosphatidylserine exposure and CD47 loss drive brain endothelial erythrophagocytosis and iron accumulation, a risk factor for dementia. Our results indicate that in human dementia, erythrocytes display increased MCP1 and reduced phospholipid fluidity, but unaltered CD47 or phosphatidylserine-recognizing-lactadherin levels.
Cancer - related anemia.
Cancer-related anemia has long been thought to be driven by impaired erythropoiesis. Our results show that cancer anemia is provoked, at least in part, through reduced CD47 and increased lactadherin. These changes could drive erythrophagocytosis and iron dysmetabolism.