人类骨髓衰竭(BMF)综合征是由于造血干细胞和祖细胞(HSPC)的丧失,这种损失归因于细胞死亡;然而,细胞死亡的触发因素,和机制仍然未知。在BMF期间,肿瘤坏死因子-α(TNFα)和干扰素-γ(IFNγ)增加。已知这些配体诱导坏死,由RIPK1、RIPK3和MLKL介导的细胞死亡的炎症形式。我们以前发现,患有造血RIPK1缺乏症(Ripk1HEMKO)的小鼠表现出炎症,HSPC损失,还有BMF,RIPK3缺乏症部分改善了;然而,RIPK3是否通过其介导坏死性凋亡或其他形式的细胞死亡的功能发挥其作用尚不清楚.这里,我们证明了类似于RIPK3缺乏症,MLKL缺乏症可显着延长生存期,而Ripk3缺乏症可部分恢复Ripk1HEMKO小鼠的造血功能,这表明这些小鼠的坏死和凋亡均有助于BMF。使用鼠标模型,我们表明,核酸传感器Z-DNA结合蛋白1(ZBP1)在小鼠RIPK1缺陷的骨髓细胞中上调,并且ZBP1在内源性核酸传感中的功能是HSPC死亡所必需的,并有助于BMF。我们还提供了IFNγ介导Ripk1HEMKO小鼠HSPC死亡的证据,因为IFNγ而不是TNFα受体信号的消融显着延长了这些小鼠的存活。一起,这些数据表明RIPK1通过阻止ZBP1激活和诱导HSPC死亡来维持造血稳态.
Human bone marrow failure (BMF) syndromes result from the loss of hematopoietic stem and progenitor cells (HSPC), and this loss has been attributed to cell death; however, the cell death triggers, and mechanisms remain unknown. During BMF, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) increase. These ligands are known to induce necroptosis, an inflammatory form of cell death mediated by RIPK1, RIPK3, and MLKL. We previously discovered that mice with a hematopoietic RIPK1 deficiency (Ripk1HEM KO) exhibit inflammation, HSPC loss, and BMF, which is partially ameliorated by a RIPK3 deficiency; however, whether RIPK3 exerts its effects through its function in mediating necroptosis or other forms of cell death remains unclear. Here, we demonstrate that similar to a RIPK3 deficiency, an MLKL deficiency significantly extends survival and like Ripk3 deficiency partially restores hematopoiesis in Ripk1HEM KO mice revealing that both necroptosis and apoptosis contribute to BMF in these mice. Using mouse models, we show that the nucleic acid sensor Z-DNA binding protein 1 (ZBP1) is up-regulated in mouse RIPK1-deficient bone marrow cells and that ZBP1\'s function in endogenous nucleic acid sensing is necessary for HSPC death and contributes to BMF. We also provide evidence that IFNγ mediates HSPC death in Ripk1HEM KO mice, as ablation of IFNγ but not TNFα receptor signaling significantly extends survival of these mice. Together, these data suggest that RIPK1 maintains hematopoietic homeostasis by preventing ZBP1 activation and induction of HSPC death.