Erythropoietin-Associated Increase in Liver Monocyte Derived Macrophages; a Role for Kupffer Cells as Mediators?

Erythropoietin (EPO) is the major hormone that drives mammalian erythropoiesis, via its surface receptor, EPO-R. It is mainly used for treating anemia associated with chronic renal failure, and certain malignancies. EPO-Rs were also found in non-erythroid cells, including dendritic cells and bone marrow macrophages (Lifshitz, 2008; 2010). Here we addressed the effect of EPO on hepatic-macrophages, namely resident liver macrophages (Kupffer cells) and liver monocyte-derived macrophages (MFs). Utilizing the rat Kupffer cell line (KCL-2) we demonstrate that these cells express EPO-R transcripts and cell surface EPO-R, as detected by our novel EPO-R antibody (GM1012; Maxwell 2015). EPO treatment of the KCL-2 cells led to a 1.5 ±0.06 fold increase in EPO-R mRNA levels and a 2±0.01 fold decrease in surface EPO-R levels. Stimulation of the cells with EPO induced a 3±0.5 fold increase in transcript levels of CCL-2 (a chemo attractant for monocytes) and a 15%±0.6 increase in the levels of the secreted chemokine. EPO treatment also enhanced cellular activity of the KCL-2 cells as manifested in a 50%±0.13 increase in cell migration, an increase in phagocytosis of microbeads (40%±0.08) and of E.coli (13%±0.05).

Finally, in vivo experiments demonstrated a specific EPO-induced selective increase (19.5% ±0.01) in MFs, but not in Kupffer cells. Elevated CCL-2 in sera of EPO-injected mice (2.1 fold increase) supports a mechanism by which EPO stimulates Kupffer cells to increase secretion of CCL-2 which enhances recruitment of monocytes to the liver and their subsequent differentiation into MFs.

The present study points to a new EPO action on two separate liver macrophages populations, thus calling for future studies on EPO effects on inflammation in the liver and in other tissues.