坏死性下垂
裂谷1
程序性细胞死亡
祖细胞
细胞生物学
淋巴细胞生成
生物
造血
骨髓
干细胞
癌症研究
免疫学
细胞凋亡
生物化学
作者
Justine Roderick-Richardson,Sung-Eun Lim,Sakiko Suzuki,Mohd Hafiz Ahmad,Jonathan Selway,Reem Suleiman,Keshab Kumar Karna,Jesse Lehman,Joanne A. O’Donnell,Lucio H. Castilla,Jonathan Maelfait,Jan Rehwinkel,Michelle A. Kelliher
标识
DOI:10.1073/pnas.2309628121
摘要
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 ( Ripk1 HEM 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 Ripk1 HEM 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 Ripk1 HEM 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.
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