Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q-syndrome
Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q-syndrome
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DOI：
10.1038/s41375-018-0350-3
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发表时间：
2019-07-01
期刊：
影响因子：
11.4
通讯作者：
Schneider, Rebekka K.
中科院分区：
文献类型：
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作者：
Ribezzo, Flavia;Snoeren, Inge A. M.;Schneider, Rebekka K.
RPS14、CSNK1A1和miR-145在5q综合征中普遍是共缺失的，但每个基因缺陷的小鼠模型仅概括了复合临床特征的一个子集。我们利用基因工程的条件杂合性失活的Rps14和Csnk1a1以及稳定的敲除miR-145/miR-146a的小鼠，分析了Rps14、Csnk1a1和miRNA-145单倍体不足的组合效应。Rps14/Csnk1a1/miR-145/146a联合缺陷概括了5q综合征的基本特征，包括(1)比Rps14单倍体功能不全更严重的贫血，动力学更快，(2)病理性巨核细胞形态。在Rps14/Csnk1a1/miR-145/146a缺陷小鼠和5q综合征患者骨髓中，作为红细胞生成和天然免疫反应调节细胞的巨噬细胞显著增加，并表现为天然免疫反应的激活，表现为S100A8表达的增加和吞噬功能的降低。我们证明了Rps14/Csnk1a1/miR-145和miR-146a缺乏的巨噬细胞改变了微环境，并诱导了间充质干细胞巢中S100A8的表达。在5q综合征患者中，S100A8在间充质龛中的表达增加。这些数据表明，5q综合征造血干细胞的内在缺陷直接改变了周围的微环境，进而作为一种外在机制影响造血。
RPS14, CSNK1A1, and miR-145 are universally co-deleted in the 5q-syndrome, but mouse models of each gene deficiency recapitulate only a subset of the composite clinical features. We analyzed the combinatorial effect of haploinsufficiency for Rps14, Csnk1a1, and miRNA-145, using mice with genetically engineered, conditional heterozygous inactivation of Rps14 and Csnk1a1 and stable knockdown of miR-145/miR-146a. Combined Rps14/Csnk1a1/miR-145/146a deficiency recapitulated the cardinal features of the 5q-syndrome, including (1) more severe anemia with faster kinetics than Rps14 haploinsufficiency alone and (2) pathognomonic megakaryocyte morphology. Macrophages, regulatory cells of erythropoiesis and the innate immune response, were significantly increased in Rps14/Csnk1a1/miR-145/146a deficient mice as well as in 5q-syndrome patient bone marrows and showed activation of the innate immune response, reflected by increased expression of S100A8, and decreased phagocytic function. We demonstrate that Rps14/Csnk1a1/miR-145 and miR-146a deficient macrophages alter the microenvironment and induce S100A8 expression in the mesenchymal stem cell niche. The increased S100A8 expression in the mesenchymal niche was confirmed in 5q-syndrome patients. These data indicate that intrinsic defects of the 5q-syndrome hematopoietic stem cell directly alter the surrounding microenvironment, which in turn affects hematopoiesis as an extrinsic mechanism.