Erythropoietin stimulates spleen BMP4-dependent stress erythropoiesis and partially corrects anemia in a mouse model of generalized inflammation.
Mouse bone marrow erythropoiesis is homeostatic, whereas after acute anemia, bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis develops in the spleen. The aim of this work was to compare spleen stress erythropoiesis and bone marrow erythropoiesis in a mouse model of zymosan-induced generalized inflammation, which induces long-lasting anemia and to evaluate the ability of erythropoietin (Epo) injections to correct anemia in this setting. The effects of zymosan and/or Epo injections on erythroid precursor maturation and apoptosis, serum interferon-γ levels, hematologic parameters, and spleen BMP4 expression were analyzed, as well as the effect of zymosan on red blood cell half-life. We found that bone marrow erythropoiesis is suppressed by inflammation and does not respond to Epo administration, despite repression of erythroblast apoptosis. On the contrary, a robust erythropoietic response takes place in the spleen after Epo injections in both control and zymosan-induced generalized inflammation mice. This specific response implies Epo-mediated induction of BMP4 expression by F4/80(+) spleen macrophages, proliferation of stress burst-forming units-erythroid, and increased number of spleen erythroblasts. It allows only partial recovery of anemia, probably because of peripheral destruction of mature red cells. It is not clear whether similar BMP4-dependent stress erythropoiesis can occur in human bone marrow after Epo injections.
Millot
Sarah
S
Inserm U773, Centre de Recherche Biomédicale Bichat Beaujon, Université Paris Diderot, Paris, France.
Andrieu
Valérie
V
Letteron
Philippe
P
Lyoumi
Saïd
S
Hurtado-Nedelec
Margarita
M
Karim
Zoubida
Z
Thibaudeau
Olivier
O
Bennada
Samira
S
Charrier
Jean-Luc
JL
Lasocki
Sigismond
S
Beaumont
Carole
C
D000740:Anemia / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D015054:Zymosan / Q000633:toxicity
D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D015054:Zymosan