Itaconate promotes the differentiation of murine stress erythroid progenitors by increasing Nrf2 activity.

1. Anti-inflammatory signals promote the transition to differentiation of stress erythroid progenitors.

2. The anti-inflammatory metabolite itaconate increases Nrf2 activity to promote the differentiation of stress erythroid progenitors.

Steady state erythropoiesis produces new erythrocytes at a constant rate to replace senescent erythrocytes removed in the spleen and liver. Inflammation caused by infection or tissue damage skews bone marrow hematopoiesis, increasing myelopoiesis at the expense of steady state erythropoiesis. To compensate for the loss of production, stress erythropoiesis is induced. Stress erythropoiesis is highly conserved between mouse and human. It utilizes a strategy different than the constant production of steady state erythropoiesis. Inflammatory signals promote the proliferation of immature stress erythroid progenitors (SEPs), which then commit to differentiation. This transition relies on signals made by niche macrophages in response to erythropoietin. Nitric oxide dependent signaling drives the proliferation of stress erythroid progenitors and production of nitric oxide must be decreased so that the progenitor cells can differentiate. Here we show that as progenitor cells transition to differentiation, increased production of the anti-inflammatory metabolite itaconate activates Nfe2l2 or Nrf2, which decreases Nos2 expression, leading to decreased nitric oxide production. Mutation of Irg1, the enzyme that catalyzes the production of itaconate, causes a delayed recovery from inflammatory anemia induced by heat killed Brucella abortus. These data show that the differentiation of stress erythroid progenitors relies on a switch to an anti-inflammatory metabolism and increased expression of pro-resolving cytokines.