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

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 but utilizes a different strategy than steady state erythropoiesis. Inflammatory signals promote the proliferation of immature stress erythroid progenitors (SEPS), which in response to erythropoietin and other signals transition to stress erythroid progenitors committed to differentiation. Here we show that TNF dependent signaling increases ROS in SEPs during the proliferation stage, however, blocking ROS production impairs their later differentiation. In addition to TNF, 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. As progenitor cells transition to differentiation, increased production of the anti-inflammatory metabolite itaconate activates Nfe2l2 or Nrf2, which inhibits 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. Loss of itaconate-dependent activation of Nrf2 is rescued in vivo by IL-10, which leads to activation of Nrf2 and differentiation. 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. Key points1. The transition to differentiation of stress erythroid progenitors requires anti-inflammatory signals. 2. The anti-inflammatory metabolite itaconate and IL-10 increase Nrf2 activity to promote the differentiation of stress erythroid progenitors.