Department of Intensive Care Unit, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China.
Department of Intensive Care Unit, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China.
Biomed Pharmacother. 2017 Feb;86:254-261. doi: 10.1016/j.biopha.2016.11.147. Epub 2016 Dec 19.
Accumulating evidences have confirmed that miRNAs have important roles in sepsis. Myeloid-derived suppressor cells (MDSCs) enhance late sepsis development through immunosuppression in mice. Here, the functions and mechanisms of miR-375 in sepsis were revealed. We found that miR-375 level was downregulated but miR-21 level was upregulated in sepsis patients and that their levels were correlated negatively. Importantly, ectopic expression of miR-375 could decrease the number of sepsis Gr1+CD11b+ MDSCs in mice. Mechanistically, miR-375 could target Janus kinase 2 (JAK2) and further impaired signal transducer and activator of transcription 3 (STAT3) in sepsis Gr1+CD11b+ MDSC. Gain and loss of function of experiments showed that upregulation or downregulation of miR-375 level could decrease or increase miR-21 level. Moreover, pretreatment of JAK2 overexpressing vector could abolish the effects of miR-375 on miR-21 level and the amount of sepsis Gr1+CD11b+ MDSCs. Therefore, our results demonstrate that miR-375 could block JAK2-STAT3 pathway and thus modulate miR-21 level, which is involved in regulation of late sepsis.
越来越多的证据证实 miRNA 在脓毒症中具有重要作用。髓系来源抑制细胞（MDSCs）通过在小鼠中免疫抑制作用增强晚期脓毒症的发展。本研究揭示了 miR-375 在脓毒症中的作用及其机制。我们发现，miR-375 在脓毒症患者中的水平下调，而 miR-21 的水平上调，且两者呈负相关。重要的是，miR-375 的异位表达可减少小鼠脓毒症 Gr1+CD11b+MDSCs 的数量。机制上，miR-375 可靶向 Janus 激酶 2（JAK2），进而损害脓毒症 Gr1+CD11b+MDSC 中的信号转导子和转录激活子 3（STAT3）。功能获得和功能丧失实验表明，miR-375 水平的上调或下调可降低或增加 miR-21 水平。此外，过表达 JAK2 载体的预处理可消除 miR-375 对 miR-21 水平和脓毒症 Gr1+CD11b+MDSCs 数量的影响。因此，我们的研究结果表明，miR-375 可阻断 JAK2-STAT3 通路，从而调节 miR-21 水平，这参与了晚期脓毒症的调控。
