LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis
LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis
复制标题
LPS 通过调节 GATA2/let-7e 轴抑制细胞凋亡来扩增 MDSC
DOI：
10.1111/imcb.12204
复制
发表时间：
2019
影响因子：
4
通讯作者：
Zhang Jinping
中科院分区：
文献类型：
--
作者：
Yang Yi;Sun Di;Zhou Ji;Tan Chensheng;Zhang Hong;Chen ZhengRong;Hao ChuangLi;Zhang Jinping
髓源性抑制细胞（MDSC）代表一组由髓样祖细胞和未成熟髓样细胞组成的未成熟髓样细胞，其可以通过抑制T细胞功能来负调节免疫应答。在小鼠中，MDSC广泛定义为CD 11b和Gr 1的表达。我们和其他人已经表明，向小鼠注射致死或亚致死剂量的脂多糖（LPS）可导致骨髓（BM）、脾脏和血液中MDSC的扩增。到目前为止，负责这种扩张的分子机制研究很少;具体来说，可能涉及的单个microRNA（miRNAs）的作用在很大程度上仍然未知。我们进行了微阵列分析，以比较从注射LPS和注射磷酸盐缓冲盐水的小鼠的BM中分选的CD 11b + Gr 1+细胞的miRNA表达谱。我们鉴定了let-7 e，其在LPS处理组中高度上调，作为LPS诱导的MDSC扩增的有效调节剂。此外，BM嵌合小鼠中let-7 e过表达导致CD 11b + Gr 1+细胞群体显著增加，这是由于细胞凋亡减少所致。进一步的研究表明，let-7 e可以直接靶向caspase-3抑制细胞凋亡，LPS刺激的MDSCs中let-7 e的上调可能是由于下调的GATA 2对let-7 e转录的抑制减轻。我们的研究结果表明，LPS通过调节GATA 2/let-7 e轴抑制细胞凋亡来扩增MDSC。
Myeloid‐derived suppressor cells (MDSCs) represent a group of immature myeloid cells composed of myeloid progenitor cells and immature myeloid cells that can negatively regulate immune responses by inhibiting T‐cell function. In mice, MDSCs are broadly defined by the expression of CD11b and Gr1. We and others have shown that injection of a lethal or sublethal dose of lipopolysaccharide (LPS) into mice could result in the expansion of MDSCs in the bone marrow (BM), spleen and blood. Until now, the molecular mechanisms responsible for this expansion are poorly studied; specifically, the roles of the individual microRNAs (miRNAs) which may be involved remain largely unknown. We performed microarray analysis to compare the miRNA expression profiles of CD11b+Gr1+cells sorted from the BM of LPS‐injected and phosphate‐buffered saline‐injected mice. We identified let‐7e, which was highly upregulated in the LPS‐treated group, as a potent regulator of LPS‐induced MDSC expansion. Furthermore, let‐7e overexpression in BM chimeric mice led to a noticeable increase in the population of CD11b+Gr1+cells, which resulted from reduced cellular apoptosis. Further studies showed that let‐7e could directly target caspase‐3 to inhibit cell apoptosis, and upregulation of let‐7e in LPS‐stimulated MDSCs could be due to the relieved repression of let‐7e transcription exerted by downregulated GATA2. Our findings suggest that LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let‐7e axis.