Increased Fanconi C expression contributes to the emergency granulopoiesis response
Increased Fanconi C expression contributes to the emergency granulopoiesis response
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DOI：
10.1172/jci69032
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发表时间：
2013-09-01
影响因子：
15.9
通讯作者：
Eklund, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Hu, Liping;Huang, Weiqi;Eklund, Elizabeth A.
紧急粒细胞生成是先天免疫应答的一个组成部分，其是响应于感染性或炎症性攻击而诱导的。其特征在于粒细胞/单核细胞祖细胞（GMP）群体的快速扩增和分化，这部分是由于细胞周期的S期缩短。我们发现，IRF 8（也称为ICSBP），一种干扰素调节转录因子，激活吞噬细胞效应基因在先天性免疫反应，激活基因编码范可尼C（Fancc）在小鼠骨髓祖细胞。此外，IRF 8诱导的Fancc转录通过用IL-β（紧急粒细胞生成的必需细胞因子）处理而增强。Fanconi通路参与DNA复制过程中停滞或塌陷的复制叉的修复，这使我们假设Fanconi通路有助于紧急粒细胞生成过程中的基因组稳定性。为了支持这一假设，Fancc（-/-）小鼠在反复的、失败的紧急粒细胞生成发作期间发生贫血和中性粒细胞减少症。Fancc（-/-）小鼠的紧急粒系造血失败与骨髓中HSC和祖细胞的过度凋亡以及HSC功能受损相关。这些研究对了解范可尼贫血骨髓衰竭的发病机制有意义，并提出了可能的治疗方法。
Emergency granulopoiesis is a component of the innate immune response that is induced in response to infectious or inflammatory challenge. It is characterized by the rapid expansion and differentiation of granulocyte/monocyte progenitor (GMP) populations, which is due in part to a shortened S-phase of the cell cycle. We found that IRF8 (also known as ICSBP), an interferon regulatory transcription factor that activates phagocyte effector genes during the innate immune response, activates the gene encoding Fanconi C (Fancc) in murine myeloid progenitor cells. Moreover, IRF8-induced Fancc transcription was augmented by treatment with IL-beta, an essential cytokine for emergency granulopoiesis. The Fanconi pathway participates in repair of stalled or collapsed replication forks during DNA replication, leading us to hypothesize that the Fanconi pathway contributes to genomic stability during emergency granulopoiesis. In support of this hypothesis, Fancc(-/-) mice developed anemia and neutropenia during repeated, failed episodes of emergency granulopoiesis. Failed emergency granulopoiesis in Fancc(-/-) mice was associated with excess apoptosis of HSCs and progenitor cells in the bone marrow and impaired HSC function. These studies have implications for understanding the pathogenesis of bone marrow failure in Fanconi anemia and suggest possible therapeutic approaches.