Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis
Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis
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DOI：
10.1182/blood-2014-04-570762
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发表时间：
2014-08-28
期刊：
影响因子：
20.3
通讯作者：
Manz, Markus G.
中科院分区：
文献类型：
--
作者：
Boettcher, Steffen;Gerosa, Rahel C.;Manz, Markus G.
全身性细菌感染诱导称为“紧急粒细胞生成”的造血反应程序，其特征在于从头增加的骨髓（BM）中性粒细胞产生。然而，局部免疫控制和细菌传播的丧失如何被感知并随后转化为从稳态到紧急粒细胞生成的转换尚不清楚。使用组织特异性骨髓分化初级反应基因88（Myd 88）缺陷小鼠和体内脂多糖（LPS）管理模型严重的细菌感染，我们在这里表明，内皮细胞（EC），但不是造血细胞，肝细胞，周细胞，或BM基质细胞，是这个过程中必不可少的细胞。事实上，来自包括BM在内的多种组织的EC表达高水平的Tlr 4和Myd 88，并且在LPS攻击或大肠杆菌感染后是粒细胞集落刺激因子（G-CSF）（关键的粒细胞生成细胞因子）的主要来源。EC-内在MYD 88信号传导和随后由EC产生的G-CSF是骨髓祖细胞谱系向粒细胞-巨噬细胞祖细胞倾斜、BM中粒细胞集落形成单位活性增加和LPS刺激后BM中性粒细胞生成加速所必需的。因此，EC催化检测全身感染进入需求适应性粒细胞生成。
Systemic bacterial infection induces a hematopoietic response program termed "emergency granulopoiesis" that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.