Phagocytosis of Erythrocytes from Gaucher Patients Induces Phenotypic Modifications in Macrophages, Driving Them toward Gaucher Cells

Abstract

Gaucher disease (GD) is caused by glucocerebrosidase deficiency leading to the accumulation of sphingolipids in macrophages named “Gaucher’s Cells”. These cells are characterized by deregulated expression of cell surface markers, abnormal secretion of inflammatory cytokines, and iron sequestration. These cells are known to infiltrate tissues resulting in hematological manifestations, splenomegaly, and bone diseases. We have already demonstrated that Gaucher red blood cells exhibit altered properties suggesting their key role in GD clinical manifestations. We hypothesized that Gaucher’s erythrocytes could be prone to premature destruction by macrophages contributing to the formation of altered macrophages and Gaucher-like cells. We conducted in vitro experiments of erythrophagocytosis using erythrocytes from Gaucher’s patients or healthy donors. Our results showed an enhanced erythrophagocytosis of Gaucher red blood cells compared to healthy red blood cells, which is related to erythrocyte sphingolipids overload and reduced deformability. Importantly, we showed elevated expression of the antigen-presenting molecules CD1d and MHC-II and of the iron-regulator hepcidin in macrophages, as well as enhanced secretion of the pro-inflammatory cytokine IL-1β after phagocytosis of GD erythrocytes. These results strongly suggested that erythrophagocytosis in GD contribute to phenotypic modifications in macrophages. This present study shows that erythrocytes-macrophages interactions may be crucial in GD pathophysiology and pathogenesis.

Impaired iron recycling from erythrocytes is an early hallmark of aging

“…Of note, patients who suffer from lysosomal storage disorder, Gaucher disease, show iron deposits in the splenic macrophages ( Clarke et al, 2021 ; Lefebvre et al, 2018 ). Iron sequestration in Gaucher macrophages was attributed to the hepcidin-mediated downregulation of ferroportin, or more recently to increased erythrophagocytosis of Gaucher RBCs ( Dupuis et al, 2022 ). Based on our study, it is plausible that defects in proteostasis, due to defective lysosomal-mediated protein quality control, may contribute to aberrant iron management in Gaucher macrophages.…”

Erythrocyte TLR9 is upregulated in metabolic associated fatty liver disease, and is linked to an inflammatory immunometabolic signature

“…However, iron alone is not sufficient for triggering ferroptosis and inflammation. Recent reports indicated that erythrocyte lipid peroxides, sphingosine and erythrocyte-bound mitochondrial DNA render erythrophagocytosis pro-inflammatory 23,42,43 . In the past, we have shown that erythrocytes of MAFLD patients contain increased sphingosine 21 .…”

Erythrocytes of Nonalcoholic Steatohepatitis Patients Contain Decreased Arginase-1 and Thrombospondin-1, and Increased Phosphatidylethanolamine Levels

“…However, various mechanisms driving erythrophagocytosis have also emerged. Reduced CD47 surface levels, binding of TSP-1 on conformationally changed CD47 [16], and sphingolipid-induced reduction of deformability [10] can result in erythrophagocytosis. We recently showed that erythrocytes of these patients also exhibit increased sphingosine levels [8].…”

“…Mechanistically, they showed that the exposed phosphatidylserine of erythrocyte membranes in NASH is partially responsible for erythrophagocytosis. Our previous results have shown that erythrocyte membranes of NASH patients also exhibit reduced levels of sphingomyelin [7] and accumulation of sphingosine [8], which can both result in phosphatidylserine exposure [9,10]. However, erythrocyte phosphatidylserine exposure can also be triggered by reduced nitric oxide levels [11].…”