Ruan Baiye, Chen Yuanting, Trimidal Sara, Koo Imhoi, Qian Fenghua, Cai Jingwei, Mcguigan John, Hall Molly A, Patterson Andrew D, Prabhu K Sandeep, Paulson Robert F
bioRxiv. 2023 Mar 11:2023.03.11.532207. doi: 10.1101/2023.03.11.532207.
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 ( or ) 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.
Nitric-oxide (NO) dependent signaling favors an anabolic metabolism that promotes proliferation and inhibits differentiation.Activation of Nfe2l2 (Nrf2) decreases NO production allowing erythroid differentiation.
炎症会使骨髓造血发生偏向，增加髓系效应细胞的生成，而稳态红细胞生成则会减少。会诱导一种代偿性应激红细胞生成反应以维持体内平衡，直至炎症消退。与稳态红系祖细胞不同，应激红系祖细胞（SEP）利用炎症刺激诱导的信号。然而，其机制基础尚不清楚。在此，我们揭示了一个依赖一氧化氮（NO）的调控网络，该网络存在于应激红细胞生成的两个阶段，即增殖以及向分化的转变阶段。在增殖阶段，未成熟的SEP和龛中的细胞增加诱导型一氧化氮合酶（或）的表达以生成NO。增加的NO重塑SEP代谢以增加合成代谢途径，这些途径驱动细胞分裂所需的核苷酸、氨基酸和其他中间体的生物合成。这种依赖NO的代谢促进细胞增殖，同时也抑制红系分化，导致大量未定向祖细胞的扩增。这些祖细胞向分化的转变由核因子红系2相关因子2（Nfe2l2或Nrf2）的激活介导。Nrf2作为一种抗炎调节因子，可降低NO的产生，从而消除依赖NO的红系抑制并允许分化。这些数据为代谢改变如何使炎症信号在分化前扩增未成熟祖细胞提供了一个范例。
依赖一氧化氮（NO）的信号传导有利于促进增殖和抑制分化的合成代谢。Nfe2l2（Nrf2）的激活降低NO的产生，从而允许红系分化。
