Promotion of Expansion and Differentiation of Hematopoietic Stem Cells by Interleukin-27 into Myeloid Progenitors to Control Infection in Emergency Myelopoiesis.
Promotion of Expansion and Differentiation of Hematopoietic Stem Cells by Interleukin-27 into Myeloid Progenitors to Control Infection in Emergency Myelopoiesis.
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DOI：
10.1371/journal.ppat.1005507
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发表时间：
2016-03
期刊：
影响因子：
6.7
通讯作者：
Yoshimoto T
中科院分区：
文献类型：
--
作者：
Furusawa J;Mizoguchi I;Chiba Y;Hisada M;Kobayashi F;Yoshida H;Nakae S;Tsuchida A;Matsumoto T;Ema H;Mizuguchi J;Yoshimoto T
应急髓系生成是由炎症诱导的造血过程，对于补充外周的髓系细胞至关重要，这对控制病原体感染至关重要。此前，干扰素（IFN）-α和IFN -γ等促炎细胞因子已被证明在造血干细胞（HSCs）和髓系祖细胞的扩增中起关键作用，从而导致成熟髓系细胞的产生，尽管也有报道称它们对造血有抑制作用。因此，感染期间应急髓系生成的分子机制仍未完全清楚。在此，我们阐明白细胞介素（IL）-6/IL -12家族细胞因子之一的IL -27在应急髓系生成中起重要作用。在骨髓的各种造血细胞中，IL -27主要且持续地仅促进谱系⁻Sca -1⁺c -Kit⁺（LSK）细胞的扩增，尤其是具有长期重建能力的长期重建造血干细胞和髓系限制性祖细胞，并与干细胞因子协同分化为髓系祖细胞。这些祖细胞通过激活信号转导和转录激活因子1和3表达髓系转录因子，如Spi1、Gfi1和Cebpa/b，并且增强了分化为迁移性树突状细胞（DCs）、中性粒细胞和肥大细胞的潜能，而分化为巨噬细胞和嗜碱性粒细胞的能力较弱，但不分化为浆细胞样DCs、常规DCs、T细胞和B细胞。在各种细胞因子中，IL -27与干细胞因子协同具有最强的增强LSK细胞扩增及其长期分化为保留LSK表型的髓系祖细胞的能力。使用IL -27受体亚单位之一WSX -1和IFN -γ缺陷小鼠进行的实验表明，疟疾感染的血液期通过产生IFN -γ增强IL -27的表达，然后IL -27促进LSK细胞的扩增，使其分化并动员到脾脏，导致中性粒细胞产生增加以控制感染。因此，IL -27是在应急髓系生成过程中直接作用于造血干细胞以促进分化为髓系祖细胞的有限的独特细胞因子之一。
应急髓系生成是由炎症诱导的造血过程，对控制病原体感染至关重要，但分子机制仍未完全清楚。在此，我们阐明白细胞介素（IL）-6/IL -12家族细胞因子之一的IL -27在应急髓系生成中起重要作用。在骨髓的各种造血细胞中，IL -27主要且持续地仅促进谱系⁻Sca -1⁺c -Kit⁺（LSK）细胞的扩增，尤其是长期重建造血干细胞，并与干细胞因子协同分化为髓系祖细胞。这些祖细胞通过激活信号转导和转录激活因子1和3表达髓系转录因子，如Spi1、Gfi1和Cebpa/b，并且增强了分化为中性粒细胞的潜能，但不分化为浆细胞样树突状细胞。在各种细胞因子中，IL -27与干细胞因子协同具有最强的增强LSK细胞扩增及其分化为髓系祖细胞的能力。疟疾感染的血液期被证明通过产生干扰素 -γ增强IL -27的表达，然后IL -27促进LSK细胞的扩增，使其分化并动员到脾脏，导致中性粒细胞产生增加以控制感染。因此，IL -27是在应急髓系生成过程中直接作用于造血干细胞以促进分化为髓系祖细胞的有限的独特细胞因子之一。
Emergency myelopoiesis is inflammation-induced hematopoiesis to replenish myeloid cells in the periphery, which is critical to control the infection with pathogens. Previously, pro-inflammatory cytokines such as interferon (IFN)-α and IFN-γ were demonstrated to play a critical role in the expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, leading to production of mature myeloid cells, although their inhibitory effects on hematopoiesis were also reported. Therefore, the molecular mechanism of emergency myelopoiesis during infection remains incompletely understood. Here, we clarify that one of the interleukin (IL)-6/IL-12 family cytokines, IL-27, plays an important role in the emergency myelopoiesis. Among various types of hematopoietic cells in bone marrow, IL-27 predominantly and continuously promoted the expansion of only Lineage−Sca-1+c-Kit+ (LSK) cells, especially long-term repopulating HSCs and myeloid-restricted progenitor cells with long-term repopulating activity, and the differentiation into myeloid progenitors in synergy with stem cell factor. These progenitors expressed myeloid transcription factors such as Spi1, Gfi1, and Cebpa/b through activation of signal transducer and activator of transcription 1 and 3, and had enhanced potential to differentiate into migratory dendritic cells (DCs), neutrophils, and mast cells, and less so into macrophages, and basophils, but not into plasmacytoid DCs, conventional DCs, T cells, and B cells. Among various cytokines, IL-27 in synergy with the stem cell factor had the strongest ability to augment the expansion of LSK cells and their differentiation into myeloid progenitors retaining the LSK phenotype over a long period of time. The experiments using mice deficient for one of IL-27 receptor subunits, WSX-1, and IFN-γ revealed that the blood stage of malaria infection enhanced IL-27 expression through IFN-γ production, and the IL-27 then promoted the expansion of LSK cells, differentiating and mobilizing them into spleen, resulting in enhanced production of neutrophils to control the infection. Thus, IL-27 is one of the limited unique cytokines directly acting on HSCs to promote differentiation into myeloid progenitors during emergency myelopoiesis. Emergency myelopoiesis is inflammation-induced hematopoiesis that is critical for controlling infection with pathogens, but the molecular mechanism remains incompletely understood. Here, we clarify that one of the interleukin (IL)-6/IL-12 family cytokines, IL-27, plays an important role in emergency myelopoiesis. Among various types of hematopoietic cells in bone marrow, IL-27 predominantly and continuously promoted expansion of only Lineage−Sca-1+c-Kit+ (LSK) cells, especially long-term repopulating hematopoietic stem cells, and differentiation into myeloid progenitors in synergy with stem cell factor. These progenitors expressed myeloid transcription factors such as Spi1, Gfi1, and Cebpa/b through activation of signal transducer and activator of transcription 1 and 3, and had enhanced potential to differentiate into neutrophils, but not into plasmacytoid dendritic cells. Among various cytokines, IL-27 in synergy with stem cell factor had the strongest ability to augment the expansion of LSK cells and their differentiation into myeloid progenitors. The blood stage of malaria infection was revealed to enhance IL-27 expression through interferon-γ production, and IL-27 then promoted the expansion of LSK cells, differentiating and mobilizing them into the spleen, resulting in enhanced production of neutrophils to control the infection. Thus, IL-27 is one of the limited unique cytokines directly acting on hematopoietic stem cells to promote differentiation into myeloid progenitors during emergency myelopoiesis.