Nitric oxide regulates metabolism in murine stress erythroid progenitors to promote recovery during inflammatory anemia

Abstract

Inflammation skews bone marrow hematopoiesis increasing the production of myeloid effector cells at the expense of steady-state erythropoiesis. A compensatory stress erythropoiesis response is induced to maintain homeostasis until inflammation is resolved. In contrast to steady-state erythroid progenitors, stress erythroid progenitors (SEPs) utilize signals induced by inflammatory stimuli. However, the mechanistic basis for this is not clear. Here we reveal a nitric oxide (NO)-dependent regulatory network underlying two stages of stress erythropoiesis, namely proliferation, and the transition to differentiation. In the proliferative stage, immature SEPs and cells in the niche increased expression of inducible nitric oxide synthase (Nos2 or iNOS) to generate NO. Increased NO rewires SEP metabolism to increase anabolic pathways, which drive the biosynthesis of nucleotides, amino acids and other intermediates needed for cell division. This NO-dependent metabolism promotes cell proliferation while also inhibiting erythroid differentiation leading to the amplification of a large population of non-committed progenitors. The transition of these progenitors to differentiation is mediated by the activation of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or Nrf2). Nrf2 acts as an anti-inflammatory regulator that decreases NO production, which removes the NO-dependent erythroid inhibition and allows for differentiation. These data provide a paradigm for how alterations in metabolism allow inflammatory signals to amplify immature progenitors prior to differentiation.

Role of Nitric Oxide in Megakaryocyte Function

“…Further, previous studies focusing on NO's impact on platelet production have modeled conditions of stress rather than steady-state thrombopoiesis, implicating a role for iNOS in this process. Indeed, analogously increased iNOS expression and NO generation have recently been identified to play a role in stress erythropoiesis [161]. Considering that NO may have both pro-and anti-apoptotic roles [162], future studies delineating the role of NOS isoforms and NO in steady-state vs. stress thrombopoiesis may also clarify whether apoptosis plays a role and what role it plays in platelet production [163,164].…”