Inflammation induces stress erythropoiesis to maintain erythroid homeostasis in response to infection

Hypoxic stress induces a systemic response designed to increase oxygen delivery to tissues. One aspect of this response is an increase in erythropoiesis, referred to as stress erythropoiesis. In contrast to bone marrow steady state erythropoiesis, which generates new erythrocytes at a constant rate to maintain homeostasis, stress erythropoiesis rapidly generates large numbers of new erythrocytes to counteract hypoxic stress. Stress erythropoiesis is best understood in mice where it is extra-medullary occurring the fetal liver and adult spleen and liver. Stress erythropoiesis utilizes progenitor cells and signals that are distinct from bone marrow steady state erythropoiesis. Our initial work showed that hypoxia was a key signal that regulated the development of stress erythroid progenitors. However, we recently observed that inflammation rapidly induces stress erythropoiesis in the spleen in the absence of anemia or tissue hypoxia. Using a sterile inflammation model and a Citrobacter rodentium infection model, we show that an increase in erythrophagocytosis by monocytes and macrophages in the spleen is the initial step inducing stress erythropoiesis. Our data show that breakdown of hemoglobin leads to increased heme dependent signaling that drives the expression of key growth factors that promote the expansion of stress erythroid progenitors. Furthermore, these signals drive the expansion of macrophages in the spleen, which enlarges the stress erythroid niche. We have extended these observations to show that erythrophagocytosis is also a key early event in the activation of stress erythropoiesis in response to hypoxic stress. These data underscore the complex interaction between stress erythroid progenitors and monocytes/macrophages that regulate their development.