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Abstract
The anemia of inflammation is related in part to abnormal erythropoiesis in bone marrow. G-CSF regulates granulopoiesis and is increased during systemic inflammation. Here, we have showed that high levels of G-CSF are associated with repression of bone marrow erythropoiesis and expansion of splenic erythropoiesis in Escherichia coli-infected mice and lipopolysaccharide-treated mice. Under lipopolysaccharide-induced systemic inflammatory conditions in mice, G-CSF neutralization with antibody alleviated the blockage of bone marrow erythropoiesis, prevented the enhancement of splenic erythropoiesis, ameliorated splenomegaly, and reduced the brittleness of spleen. We further demonstrated that after lipopolysaccharide treatment, TLR4-knockout mice display low levels of G-CSF, healthy bone marrow erythropoiesis, almost no stress erythropoiesis in the spleen, and normal size and toughness of spleen. In addition, we found HIF-mediated erythropoietin production is essential for splenic erythropoiesis in the setting of G-CSF-induced suppression of bone marrow erythropoiesis. Our findings identify G-CSF as a critical mediator of inflammation-associated erythropoiesis dysfunction in bone marrow and offer insight into the mechanism of G-CSF-induced splenic erythropoiesis. We provide experimentally significant dimension to the biology of G-CSF.
Highlights
G-CSF, one of the lineage-specific hematopoietic cytokines, regulates the production of neutrophilic granulocyte [1, 2, 3]
We found that the percentage of Ter119+CD71+ cells in the bone marrow of mice gradually decreased with increasing doses of G-CSF (Fig 1C and D)
After G-CSF treatment (50 μg/kg), serum EPO levels in mice increased from 125 to 304 pg/ml (Fig 6A); in keeping with this result, we found that G-CSF treatment resulted in elevated EPO mRNA levels in the from control and G-CSF-treated mice (×100 magnification; scale bar = 200 μm). (L) Quantification of burst-forming unit erythroid-derived colonies in cultures of splenocytes from control and G-CSF–treated mice. (M) GATA-1 expression of splenocyte was measured by flow cytometry, and the representative histograms were shown. (N) Bar graphs showing mean fluorescence intensities. (O) Peripheral blood hematologic parameters of sham-operated mice, splenectomized mice, sham-operated mice treated with G-CSF, and splenectomized mice treated with G-CSF
Summary
G-CSF, one of the lineage-specific hematopoietic cytokines, regulates the production of neutrophilic granulocyte [1, 2, 3]. G-CSF is routinely used to mobilize hematopoietic stem and progenitor cells from the bone marrow into the peripheral blood for collection and transplantation [10]. Infection-related inflammation suppresses bone marrow erythropoiesis and enhances splenic erythropoiesis [14, 15, 16, 17, 18]. These studies and our previous findings prompted us to hypothesize G-CSF is a key molecular regulator that induces functional changes in erythropoiesis in the bone marrow and spleen under inflammatory conditions
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