Cutting Edge: Hematopoietic Stem Cell Expansion and Common Lymphoid Progenitor Depletion Require Hematopoietic-Derived, Cell-Autonomous TLR4 in a Model of Chronic Endotoxin.
Cutting Edge: Hematopoietic Stem Cell Expansion and Common Lymphoid Progenitor Depletion Require Hematopoietic-Derived, Cell-Autonomous TLR4 in a Model of Chronic Endotoxin.
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DOI：
10.4049/jimmunol.1501231
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发表时间：
2015-09-15
期刊：
影响因子：
--
通讯作者：
Borghesi L
中科院分区：
文献类型：
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作者：
Liu A;Wang Y;Ding Y;Baez I;Payne KJ;Borghesi L
造血干细胞和祖细胞（HSPCs）在体外通过toll样受体4 （TLR4）激活。然而，目前尚不清楚HSPCs在体内是直接还是通过其他细胞中间体感应TLR4。在这里，我们研究了慢性低剂量脂多糖（LPS）模型中小鼠造血干细胞（HSC）扩增和共同淋巴样祖细胞（CLP）耗竭的细胞机制。使用过继性转移方法，我们发现HSC和CLP对慢性LPS的敏感性取决于造血来源的细胞亚群自主TLR4。与小鼠祖细胞一样，人造血干细胞在体外也可被TLR4激活。使用人源化小鼠（一种与人体生理学相关的临床前模型），我们发现持续性内毒素增加了Ki-67+ hsc的频率，并严重消耗CLPs和B前体。总之，我们的研究结果表明，小鼠HSPCs在体内直接对内毒素作出反应，而持续的LPS（几种具有全球健康意义的疾病的特征）会损害人类淋巴系统。
Hematopoietic stem and progenitors cells (HSPCs) are activated through toll-like receptor 4 (TLR4) in vitro. However, it remains unclear whether in vivo TLR4 sensing by HSPCs occurs directly or via other cell intermediates. Here, we examine the cellular mechanisms underlying murine hematopoietic stem cell (HSC) expansion and common lymphoid progenitor (CLP) depletion in a model of chronic low-dose lipopolysaccharide (LPS). Using adoptive transfer approaches, we show that HSC and CLP sensitivity to chronic LPS depends on hematopoietic-derived, cell subset-autonomous TLR4. Like murine progenitors, human HSPCs are activated by TLR4 in vitro. Using humanized mice, a pre-clinical model relevant to human physiology, we show that persistent endotoxin increases the frequency of Ki-67+ HSCs, and severely depletes CLPs and B precursors. Together, our findings show that murine HSPCs directly respond to endotoxin in vivo and that persistent LPS, a feature of several diseases of global health significance, impairs human lymphopoiesis.