Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.
Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.
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DOI：
10.1038/ncb3346
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发表时间：
2016-06
影响因子：
21.3
通讯作者：
Passegué E
中科院分区：
文献类型：
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作者：
Pietras EM;Mirantes-Barbeito C;Fong S;Loeffler D;Kovtonyuk LV;Zhang S;Lakshminarasimhan R;Chin CP;Techner JM;Will B;Nerlov C;Steidl U;Manz MG;Schroeder T;Passegué E
造血干细胞(HSC)维持终生的血液生产，增加血细胞数量，以应对慢性和急性损伤。然而，炎性侮辱传递给HSC的机制(S)及其对HSC活动的影响在很大程度上仍不清楚。在这里，我们证明了白介素1(IL-1)，作为一个关键的促炎‘紧急’信号，通过早熟激活依赖于PU.1的基因程序，直接加速了HSCs的细胞分裂和髓样分化。虽然这种效应对于急性骨髓损伤(BM)后快速的髓系恢复是必不可少的，但长期的IL-1暴露限制了HSC的谱系输出，严重侵蚀了HSC的自我更新能力，并使暴露于IL-1的HSC无法通过大规模的复制挑战，如移植。重要的是，这些破坏性影响是暂时的，在IL-1停用后完全可逆。我们的结果确定了一个关键的调节回路，该回路根据急性需求定制HSC反应，并可能是慢性炎症条件下解除调节的血液动态平衡的基础。
Haematopoietic stem cells (HSC) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory ‘emergency’ signal, directly accelerates cell division and myeloid differentiation of HSCs via precocious activation of a PU.1-dependent gene program. While this effect is essential for rapid myeloid recovery following acute injury to the bone marrow (BM), chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges like transplantation. Importantly, these damaging effects are transient and fully reversible upon IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and likely underlies deregulated blood homeostasis in chronic inflammation conditions.