Abstract
Erythropoietin (EPO) is the main hormone driving mammalian erythropoiesis, with activity mediated via the surface receptor, EPO-R, on erythroid progenitor cells. Recombinant human EPO is currently used clinically for the treatment of anemia in patients with end-stage renal disease, and in certain cancer patients suffering from anemia induced either by the tumor itself or by chemotherapy. EPO-R expression is also detected in non-erythroid cells, including macrophages present in the peritoneum, spleen, and bone marrow (BM). Here we demonstrate that Kupffer cells (KCs) - the liver-resident macrophages - are EPO targets. We show that, in vitro, EPO initiated intracellular signalling and enhanced phagocytosis in a rat KC line (RKC-2) and in sorted KCs. Moreover, continuous EPO administration in mice, resulted in an increased number of KCs, up-regulation of liver EPO-R expression and elevated production of the monocyte chemoattractant CCL2, with corresponding egress of Ly6Chi monocytes from the BM. In a model of acute acetaminophen-induced liver injury, EPO administration increased the recruitment of Ly6Chi monocytes and neutrophils to the liver. Taken together, our results reveal a new role for EPO in stimulating KC proliferation and phagocytosis, and in recruiting Ly6Chi monocytes in response to liver injury.
Highlights
Erythropoietin (EPO) is the main hormone that drives mammalian erythropoiesis in response to hypoxia, through activation of the hypoxia inducible factor HIF-21
We and others have shown that macrophages from the spleen, peritoneum[26] and BM27–29 express functional EPO-Rs and they respond to treatment with EPO
To address the question of whether Kupffer cells (KCs) respond to EPO, we initially utilized the rat Kupffer cell line, RKC-2, as a model system[30]
Summary
Erythropoietin (EPO) is the main hormone that drives mammalian erythropoiesis in response to hypoxia, through activation of the hypoxia inducible factor HIF-21 It is synthesized by the adult kidney and by the fetal liver as well as by the adult liver[2, 3] and regulates the production of red blood cells via its receptor, EPO-R. Kupffer cells (KCs) are the largest population of resident macrophages in the body and their primary function is to protect the liver from bacterial infections. Their location within the sinusoidal vascular space, predominantly in the periportal area, places these cells in the perfect position to clear gut-derived bacteria, endotoxins, debris, and metabolic waste arriving at the liver via the portal vein[22, 23]. EPO stimulates KC-mediated attraction of CCR2+Ly6Chi monocytes to the challenged liver via the production of their chemoattractant - CCL2
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