Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland; International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
Cell Stem Cell. 2017 Aug 3;21(2):225-240.e5. doi: 10.1016/j.stem.2017.06.013. Epub 2017 Jul 20.
Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity. This process is mediated via TLR4-TRIF-ROS-p38, but not MyD88 signaling, and can be inhibited pharmacologically without preventing emergency granulopoiesis. Live Salmonella Typhimurium infection similarly induces proliferative stress in HSCs, in part via TLR4-TRIF signals. Thus, while direct TLR4 activation in HSCs might be beneficial for controlling systemic infection, prolonged TLR4 signaling has detrimental effects and may contribute to inflammation-associated HSPC dysfunction.
细菌感染导致寿命短暂的先天免疫效应细胞消耗，然后需要从造血干细胞和祖细胞 (HSPCs) 中补充。HSPCs 表达模式识别受体，如 Toll 样受体 (TLRs)，这些受体的连接诱导 HSPC 动员、细胞因子产生和髓样分化。涉及 HSCs 中病原体信号转导的潜在机制以及由此产生的生物学后果仍未明确定义。在这里，我们表明，体内脂多糖 (LPS) 应用直接通过 TLR4 诱导休眠 HSC 的增殖，并且持续的 LPS 暴露会损害 HSC 的自我更新和竞争再殖活性。这个过程是通过 TLR4-TRIF-ROS-p38 介导的，而不是 MyD88 信号，并且可以通过药理学抑制而不防止紧急粒状细胞生成。活鼠伤寒沙门氏菌感染同样会导致 HSCs 中的增殖应激，部分是通过 TLR4-TRIF 信号。因此，虽然 HSCs 中的直接 TLR4 激活可能有利于控制全身感染，但延长的 TLR4 信号具有有害影响，并可能导致与炎症相关的 HSPC 功能障碍。
