Hypoxia leads both to secondary polycythemia and activation of the complement (C) cascade in bone marrow (BM). We reported that C is activated in BM during hypoxia by the IgM-dependent classical pathway (

). These observations prompted us to study the potential role of C cleavage fragments in erythropoiesis. We noticed that human and murine cells from the erythroid lineage express functional G-protein coupled C3aR and that C3 cleavage fragment - anaphylatoxin C3a enhances SDF-1-mediated chemotaxis of erythroid progenitors and induces in normal erythroblasts i) adhesion to fibronectin, ii) calcium flux and iii) phosphorylation of MAPKp42/44. To further explore a potential role of the C3a-C3aR axis in erythropoiesis we focused on C3aR−/ − mice. We noticed that these animals as compared to wild type (wt) littermates have i) lower hematocrits and ii) display delayed recovery of hematocrit values after sublethal irradiation. More importantly, we noticed that the number of clonogeneic BFU-E progenitors in BM of C3aR−/ − mice, but not CFU-GM and CFU-Meg, is reduced by ~65%. Thus, in order to learn more about the role of the C3a-C3aR axis in erythropoiesis we moved to an in vitro model and costimulated normal human CD34+ or murine SKL cells with C3a or desArgC3a in the presence of suboptimal doses of EpO and KL, but no effect on BFU-E colony formation was observed. We found, however, that C3a increases in early erythroid cells expression of mRNA for VEGF and MMP-2 - which are important for maturation/enucleation and egress of erythrocytes from the BM into peripheral blood. These data were subsequently confirmed by ELISA (VEGF) and zymography (MMP-2). Furthermore, we noticed that at the morphological level C3aR−/ − mice as compared to wt littermates had significantly reduced number of erytropoietic islands in BM. This suggests that in the absence of the C3aR, maturing erythroblasts do not traffic properly in the marrow microenvironment in BM and do not associate with C3 producing central macrophages in erythropoietic islands. In conclusion the C3a-C3aR axis modulates the interaction of erythroid progenitors with the hematopoietic environment and we conclude that it plays an important and underappreciated role in developmental trafficking of erythroid cells in BM. Thus C3a may enhance the erythropoietic effects of erythropoietin in polycythemias related to hypoxia. Furthermore, since hypoxia activates C, we postulate that C cleavage fragments could be involved in the pathogenesis of hypoxia-related polycythemias and C3aR antagonists could find a potential supportive role in controlling erythropoiesis in these patients.

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