Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis.
Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis.
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DOI：
10.1007/s00401-016-1621-6
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发表时间：
2017-01
影响因子：
12.7
通讯作者：
Piccio L
中科院分区：
文献类型：
--
作者：
Cantoni C;Cignarella F;Ghezzi L;Mikesell B;Bollman B;Berrien-Elliott MM;Ireland AR;Fehniger TA;Wu GF;Piccio L
髓源性细胞在多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）中发挥重要的调节和效应作用。髓源性抑制细胞（myeloid -derived suppressor cells, MDSCs）是由单核细胞（monocytic， MO）和多形核（polymorphonuclear， PMN）组成的未成熟髓系细胞，可抑制EAE中T细胞的活性。它们在多发性硬化症中的作用仍不清楚。我们发现，与健康受试者相比，MS中循环MDSCs的数量减少，这是由于MO-MDSCs的频率较低，以及microRNA miR-223的MDSC表达较高。为了获得机制上的见解，我们询问了EAE模型。与同窝对照相比，MiR-223敲除（MiR-223−/−）小鼠出现较轻的EAE，脾脏和脊髓中MDSC数量增加。MiR-223−/−MO-MDSCs比野生型MO-MDSCs更能抑制体外T细胞增殖和细胞因子产生，以及体内EAE。它们还显示出MDSC抑制功能的关键介质Arginase-1（Arg1）和信号换能器和转录激活因子3 （Stat3）的表达增加，在这里，我们证明了它是miR-223的靶基因。与健康对照相比，来自MS患者的MDSCs显示STAT3和ARG1表达降低，这表明MS中循环MDSCs不仅数量减少，而且抑制作用也较弱。这些结果支持了miR-223在EAE和MS中调节MDSC生物学中的关键作用，并提出了潜在的新治疗应用。
Myeloid-derived cells play important modulatory and effector roles in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, composed of monocytic (MO) and polymorphonuclear (PMN) fractions, which can suppress T cell activities in EAE. Their role in MS remains poorly characterized. We found decreased numbers of circulating MDSCs, driven by lower frequencies of the MO-MDSCs, and higher MDSC expression of microRNA miR-223 in MS versus healthy subjects. To gain mechanistic insights, we interrogated the EAE model. MiR-223 knock out (miR-223−/−) mice developed less severe EAE with increased MDSC numbers in the spleen and spinal cord compared to littermate controls. MiR-223−/− MO-MDSCs suppressed T cell proliferation and cytokine production in vitro and EAE in vivo more than wild-type MO-MDSCs. They also displayed an increased expression of critical mediators of MDSC suppressive function, Arginase-1(Arg1), and the signal transducer and activator of transcription 3 (Stat3), which herein, we demonstrate being an miR-223 target gene. Consistently, MDSCs from MS patients displayed decreased STAT3 and ARG1 expression compared with healthy controls, suggesting that circulating MDSCs in MS are not only reduced in numbers but also less suppressive. These results support a critical role for miR-223 in modulating MDSC biology in EAE and in MS and suggest potential novel therapeutic applications.