Erythropoietin Dependent Signaling In Erythroblastic Island Macrophages Induces Pge2 Dependent Differentiation Of Stress Erythroid Progenitors

Inflammation caused by infection or tissue damage has a profound effect on hematopoiesis. Pro-inflammatory cytokines skew hematopoiesis to increase the production of myeloid effector cells, but this change comes with a cost as erythropoiesis is inhibited by these signals. In order to compensate for the decrease in steady state erythropoiesis, stress erythropoiesis is induced. This process is distinct from steady sate erythropoiesis and shares many properties with other stem cell mediated tissue regenerative responses. It is conserved between mouse and human. Unlike steady state erythropoiesis which constantly produces new erythrocytes, the strategy of stress erythropoiesis is to produce a bolus of erythrocytes that will maintain homeostasis until steady state erythropoiesis can resume. Previous work showed that immature stress erythroid progenitors rapidly proliferate but do not differentiate, which generates a transient amplifying population of progenitors. These progenitors develop in close contact with macrophages in structures known as erythroblastic islands (EBIs). Erythropoietin (Epo) dependent signaling in EBI macrophages changes the signals made by the macrophages from those promoting proliferation (Wnt and Hedgehog) to those promoting differentiation (PGJ2 and PGE2). Here we report that PGE2 dependent mobilization of intracellular calcium activates the Perk kinase (Eif2ak3) mediated integrated stress pathway in stress erythroid progenitors. This pathway acts to increase the expression of amino acid transporters and tRNA synthases resulting in the activation of the mTorC1 complex. These two pathways drive the commitment to erythroid differentiation and are required for the generation of new erythrocytes that will maintain homeostasis until steady state erythropoiesis can resume.