IL-6 Generated from Human Hematopoietic Stem and Progenitor Cells through TLR4 Signaling Promotes Emergency Granulopoiesis by Regulating Transcription Factor Expression
IL-6 Generated from Human Hematopoietic Stem and Progenitor Cells through TLR4 Signaling Promotes Emergency Granulopoiesis by Regulating Transcription Factor Expression
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DOI：
10.4049/jimmunol.2100168
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发表时间：
2021-08-15
影响因子：
4.4
通讯作者：
Takahashi, Naoto
中科院分区：
文献类型：
--
作者：
Sasaki, Yumi;Guo, Yong-Mei;Takahashi, Naoto
紧急粒细胞生成，也称为需求适应性粒细胞生成，被定义为生物体对全身性细菌感染的反应，它导致中性粒细胞从储库中动员，并增加骨髓中的骨髓生成。紧急粒细胞生成的间接和直接启动机制已被假设。然而，骨髓中的骨髓增生过度活跃导致粒细胞左移的详细机制仍不清楚。在这项研究中，我们报告了TLR 4在粒单核细胞祖细胞以及动员的人外周血CD 34（+）细胞上表达，其占外周血单核细胞的0.2%，与骨髓中的10%相似。LPS是导致全身性细菌感染的革兰氏阴性菌的一种组分，其通过TLR 4信号通路在体外诱导外周血CD 34（+）细胞分化为骨髓细胞和单核细胞。此外，CD 34（+）细胞通过激活MAPK和NF-κ B信号通路直接响应LPS刺激，并且它们产生通过磷酸化C/EBP α和C/EBP β促进紧急粒细胞生成的IL-6，并且这种作用被IL-6受体抑制剂的作用抑制。这项工作支持了TLR在人类造血干细胞和祖细胞上表达的发现，并且它提供了证据，证明人类造血干细胞和祖细胞可以直接感知病原体并产生发挥自分泌和/或旁分泌作用的细胞因子，从而促进分化。
Emergency granulopoiesis, also known as demand-adapted granulopoiesis, is defined as the response of an organism to systemic bacterial infections, and it results in neutrophil mobilization from reservoir pools and increased myelopoiesis in the bone marrow. Indirect and direct initiating mechanisms of emergency granulopoiesis have been hypothesized. However, the detailed mechanism of hyperactive myelopoiesis in the bone marrow, which leads to granulocyte left shift, remains unknown. In this study, we report that TLR4 is expressed on granulo-monocytic progenitors, as well as mobilized human peripheral blood CD34(+) cells, which account for 0.2% of monocytes in peripheral blood, and similar to 10% in bone marrow. LPS, a component of Gram-negative bacteria that results in a systemic bacterial infection, induces the differentiation of peripheral blood CD34(+) cells into myelocytes and monocytes in vitro via the TLR4 signaling pathway. Moreover, CD34(+) cells directly responded to LPS stimulation by activating the MAPK and NF-kappa B signaling pathways, and they produced IL-6 that promotes emergency granulopoiesis by phosphorylating C/EBP alpha and C/EBP beta, and this effect was suppressed by the action of an IL-6 receptor inhibitor. This work supports the finding that TLR is expressed on human hematopoietic stem and progenitor cells, and it provides evidence that human hematopoietic stem and progenitor cells can directly sense pathogens and produce cytokines exerting autocrine and/or paracrine effects, thereby promoting differentiation.