Involvement of cross-linked ribosomal protein S19 oligomers and C5a receptor in definitive erythropoiesis

• An extraribosomal role of ribosomal protein S19 in erythropoiesis is proposed.
• Ribosomal protein S19 oligomers are present in extracellular fluid of bone marrow.
• The marrow oligomer concentration is increased in association to hypererythropoiesis.
• Neutralization of the marrow oligomers retards blood loss-induced anemic state.
• Erythroblasts in normal human bone marrow express the C5a receptor gene.

We performed a series of experiments under a working hypothesis that cross-linked oligomers of ribosomal protein S19 (RP S19) play an essential role in definitive erythropoiesis as a ligand of the C5a receptor of erythroblasts and macrophages. We found molecules functionally and immunologically indistinguishable from RP S19 oligomers in the extracellular fluid of porcine and guinea pig bone marrow. When an increased hematopoietic state was induced in guinea pigs by bloodletting, the bone marrow RP S19 oligomer concentration was concomitantly increased. However, when the RP S19 oligomers were immunologically neutralized or the C5a receptor was pharmacologically antagonized, hyper-erythropoiesis induced by bloodletting was prevented and the anemic state was retarded in guinea pigs. When the RP S19 oligomers were neutralized in mice after bloodletting, the reactive hyper proliferation of erythroblasts in the spleen was prevented. Proerythroblasts and erythroblasts prepared by bone marrow aspiration from healthy individuals were found to express significant levels of the C5a receptor and type 2 transglutaminase genes. Majority of erythroblasts in cord blood of healthy newborns bore the C5a receptor. Taken together, these results support our hypothesis.