Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion
Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion
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DOI：
10.1038/nm.1973
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发表时间：
2009-06-01
期刊：
影响因子：
82.9
通讯作者：
Ohteki, Toshiaki
中科院分区：
文献类型：
--
作者：
Sato, Taku;Onai, Nobuyuki;Ohteki, Toshiaki
I型干扰素(IFN)是一类细胞因子，可协调许多生物和细胞过程(1-3)。虽然众所周知，I型干扰素对于建立宿主抗病毒状态是必不可少的(4)，但它们在造血稳态中的作用还没有被研究过。在这里，我们证明了I型干扰素诱导造血干细胞(HSCs)的增殖和衰竭，而I型干扰素信号(5，6)的转录抑制因子-2(IRF2)保留了HSCs的自我更新和多系分化能力。与irf2(+/-)小鼠相比，irf2(-/-)小鼠骨髓中的HSCs数量要少得多。IRF2(-/-)HSCs在竞争性再增殖实验中表现为细胞周期状态增强，不能产生造血细胞，通过阻断I型干扰素信号可恢复IRF2(-/-)HSCs的重建能力。在野生型小鼠中，注射I型干扰素信号的诱导剂聚(I：C)或干扰素-α诱导HSC增殖，以及慢性I型干扰素信号进一步减少静止的HSC数量。值得注意的是，聚(I：C)和5-氟尿嘧啶(5-FU)联合治疗允许外源性HSC在WT小鼠中植入和造血重建。我们的发现为维持HSC静止的分子基础提供了洞察力，并可能导致骨髓移植和基于I型干扰素的病毒感染和癌症治疗的改进。
Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes(1-3). Although it is well known that type I IFNs are essential for establishing the host antiviral state(4), their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling(5,6), preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2(-/-) as compared to Irf2(+/-) mice. Irf2(-/-) HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2(-/-) HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN-alpha induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN-based therapies for viral infection and cancer.