IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors
IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors
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DOI：
10.1182/blood-2011-06-364976
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发表时间：
2012-03-01
期刊：
影响因子：
20.3
通讯作者：
Bhattacharya, Deepta
中科院分区：
文献类型：
--
作者：
Becker, Amy M.;Michael, Drew G.;Bhattacharya, Deepta
虽然大多数血液谱系被认为是通过HSC下游的单一细胞和发育途径成熟的，但树突状细胞（DC）可以在体内来源于骨髓和淋巴祖细胞。为了确定不同的祖细胞如何产生相似的下游谱系，我们检查了伴随体内髓样潜能丧失的转录变化，如普通髓样祖细胞分化为普通DC祖细胞（CDPs），以及淋巴致敏的多能祖细胞（LMPPs）分化为所有淋巴样祖细胞（ALP）。微阵列研究表明，IFN调节因子8（IRF-8）的表达增加，在每个这些过渡。使用Irf 8（-/-）BM的竞争性重建证明了CDPs和所有脾DC亚群形成中的细胞内在缺陷。Irf 8（-/-）共同髓系祖细胞和Irf 8（-/-）ALP在体内产生比其野生型对应物更多的嗜中性粒细胞，这是以DC为代价的。逆转录病毒表达的IRF-8在多个祖细胞导致减少中性粒细胞的生产和增加的DC数量，甚至在粒细胞-巨噬细胞祖细胞（GMP），这通常不具有传统的DC潜力。这些数据表明，IRF-8抑制中性粒细胞模块的发展，并促进会聚DC发展从多个淋巴和骨髓祖细胞自主的细胞环境。（血。2012; 119（9）：2003-2012）
While most blood lineages are assumed to mature through a single cellular and developmental route downstream of HSCs, dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors differentiate into common DC progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that IFN regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8(-/-) BM demonstrated cell-intrinsic defects in the formation of CDPs and all splenic DC subsets. Irf8(-/-) common myeloid progenitors and, unexpectedly, Irf8(-/-) ALPs produced more neutrophils in vivo than their wild-type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context. (Blood. 2012; 119(9): 2003-2012)