Erythroblastic Island Macrophages in SCD Disordered Erythropoiesis.

New York Blood Center, New York NY

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Abstract

Erythroblastic island macrophages (EBI M) are niche cells for erythropoiesis. Alterations in EBI M contribute to the disordered erythropoiesis in various hematological diseases. We have documented that EBI M are characterized by the expression of erythropoietin receptor (EPOR) and that EPO/EPOR signaling in EBI M promotes EBI formation and enucleation of erythroblasts. Recently we found that the ability of SCD mice BM to compensate for anemia was impaired as demonstrated by the very limited increase in erythroid progenitors and their diminished colony formation ability. We also have documented that downregulation of PPAR was responsible for heme-driven proinflammatory switch and defective phagocytic activity of hepatic M in SCD. Our preliminary data show that in SCD mice and hemin-treated mice, orthochromatic erythroblasts were accumulated in the BM indicative of impaired erythroblast enucleation, EBI M were switched to proinflammatory phenotype and EPO-stimulated Stat5 in EBI M was severely diminished, along with downregulation of PPAR and upregulation of proinflammatory chemokine CCL8/CXCL16 which recruit IL-1 expressing granulocytes and IFN-expressing T cells to EBIs. Additionally, the expression of growth factors IGF1 and SCF in EBI M was decreased SCD mice and hemin-treated mice. Our overall hypothesis is that hemolysis impairs the ability of EBI M to support erythropoiesis in SCD by inhibition of EPO/EPOR signaling pathways which can be reversed by transfusions or/and heme scavenger treatment. In Aim 1A we will define the mechanisms for the increased production of CCL/CXCL16 by EBI  and their role in the impaired erythroid progenitor in SCD with the hypothesis that hemolysis-mediated activation of TLR4/NFkB leads to inhibition of EPO/EPOR-PPAR axis in SCD EBI  increasing CCL8- and CXCL16-driven recruitment of IL-1 expressing granulocytes and IFN- expressing T cells to EBIs, inhibiting erythroid progenitor proliferation In Aim 1B we will define the mechanisms and contribution of decreased IGF1/SCF production by the EBI  to the impaired erythroid progenitor with the hypothesis that decreased production of IGF1/SCF due to hemolysis-driven inhibition of EPO/EPOR signaling contributes to the impaired erythroid progenitor in SCD. In Aim 2A, we will define the mechanisms and role of defective phagocytotic ability of EBI M in the impaired enucleation in SCD with the hypothesis that hemolysis driven inhibition of EPO/EPOR-PPAR signaling in EBI M diminishes their ability to engulf extruded nuclei, contributing to impaired enucleation. In Aim 2B, we will define the mechanisms and contribution of defective efferocytosis by the EBI M to the impaired erythropoiesis with the hypothesis that decreased efferocytosis due to hemolysis-driven inhibition of EPO/EPOR signaling contributes to an inflammatory BM environment and impaired erythroid progenitor. For all the Aims, we will examine the therapeutic potential of transfusions, hemopexin and PPAR agonists. Our findings will not only provide novel insights into the role of EBI M in the disordered erythropoiesis of SCD and BM inflammation but also have implications in the treatment of the disease.