ZBP1 activation triggers hematopoietic stem and progenitor cell death resulting in bone marrow failure in mice

• 成果类型: Article
• 署名作者: Roderick-Richardson, Justine E.; Lim, Sung-Eun; Suzuki, Sakiko; Ahmad, Mohd Hafiz; Selway, Jonathan; Suleiman, Reem; Karna, Keshab; Lehman, Jesse; O'Donnell, Joanne; Castilla, Lucio H.; Maelfait, Jonathan; Rehwinkel, Jan; Kelliher, Michelle A.
• 署名单位: University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Monash University; Ghent University; Flanders Institute for Biotechnology (VIB); University of Oxford
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14717
• DOI: 10.1073/pnas.2309628121
• 发表日期: 2024-01-23
• 关键词: ripk1; necroptosis; rna; apoptosis; necrosis; domain; adar1; inflammation; lethality

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-alpha (TNF alpha) and interferon-gamma (IFN gamma) 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 IFN. mediates HSPC death in Ripk1HEM KO mice, as ablation of IFN. but not TNFa 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.